Method for treating depression and/or depression status with substituted quinoxaline compounds

ABSTRACT

A heterocyclic compound represented by the general formula (1) or a salt thereof: 
     
       
         
         
             
             
         
       
         
         wherein m, l, and n respectively represent an integer of 1 or 2; X represents —O— or —CH 2 —; 
         R 1  represents hydrogen, a lower alkyl group, a hydroxy-lower alkyl group, a protecting group, or a tri-lower alkylsilyloxy-lower alkyl group; 
         R 2  and R 3 , which are the same or different, each independently represent hydrogen or a lower alkyl group; or R 2  and R 3  are bonded to form a cyclo-C3-C8 alkyl group; and 
         R 4  represents an aromatic group or a heterocyclic group, wherein 
         the aromatic or heterocyclic group may have one or more arbitrary substituent(s).

This is a continuation of application Ser. No. 14/705,870, filed May 6,2015, which is a divisional application of application Ser. No.13/822,589, filed May 29, 2013, now U.S. Pat. No. 9,090,572, issued Jul.28, 2015, which is a National Stage of PCT/JP2011/071174, filed Sep. 12,2011, and claims foreign priority to JP 2010-204747, filed Sep. 13,2010, all of which are incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to a novel heterocyclic compound.

BACKGROUND ART

Three monoamines known as serotonin, norepinephrine, and dopaminefunction as neurotransmitters in vivo. Therefore, drugs havinginhibitory effects on the reuptake of these monoamines have been usedwidely as therapeutic drugs for diseases associated with the central orperipheral nervous system.

Most of drugs previously used in the treatment of depression selectivelyinhibit the reuptake of norepinephrine or serotonin. Examples of suchdrugs include imipramine (first-generation antidepressant), maprotiline(second-generation antidepressant), selective serotonin reuptakeinhibitors (SSRIs, third-generation antidepressants) typified byfluoxetine, and serotonin and/or norepinephrine reuptake inhibitors(SNRIs, fourth-generation antidepressants) typified by venlafaxine (S.Miura, Japanese Journal of Clinical Psychopharmacology, 2000, 3:311-318).

However, all of these drugs require a period as long as 3 weeks orlonger for exerting their therapeutic effects and, in addition, fail toexert sufficient therapeutic effects on approximately 30% of patientswith depression (Phil Skolnick, European Journal of Pharmacology, 1999,375: 31-40).

DISCLOSURE OF INVENTION

An object of the present invention is to provide a drug that has a widetherapeutic spectrum and can exert sufficient therapeutic effects in ashort period, compared with antidepressants known in the art.

The present inventors have conducted diligent studies to attain theobject and have consequently found that a heterocyclic compoundrepresented by the general formula (1) shown below can be used in theproduction of the desired drug. The present invention has been completedbased on these findings.

The present invention provides a heterocyclic compound or a salt thereofaccording to any one of Items 1 to 15 shown below, a pharmaceuticalcomposition comprising the compound or an use of the compounds, a methodfor treating or preventing diseases or a methods for producing thecompounds.

-   Item 1. A heterocyclic compound represented by the general    formula (1) or a salt thereof:

-   wherein m, l, and n respectively represent an integer of 1 or 2; X    represents —O— or —CH₂—;-   R¹ represents hydrogen, a lower alkyl group, a hydroxy-lower alkyl    group, a protecting group, or a tri-lower alkylsilyloxy-lower alkyl    group;-   R² and R³, which are the same or different, each independently    represent hydrogen or a lower alkyl group; or R₂ and R₃ are bonded    to form a cyclo-C3-C8 alkyl group; and-   R⁴ represents an aromatic group or a heterocyclic group, wherein-   the aromatic or heterocyclic group may have one or more arbitrary    substituent(s).-   Item 2. The heterocyclic compound represented by the general    formula (1) or a salt thereof according to item 1, wherein-   R⁴ represents any of-   (1) a phenyl group,-   (2) an indolyl group,-   (3) a benzothienyl group,-   (4) a naphthyl group,-   (5) a benzofuryl group,-   (6) a quinolyl group,-   (7) an isoquinolyl group,-   (8) a pyridyl group,-   (9) a thienyl group,-   (10) a dihydrobenzoxazinyl group,-   (11) a dihydrobenzodioxinyl group,-   (12) a dihydroquinolyl group,-   (13) a chromanyl group,-   (14) a quinoxalinyl group,-   (15) a dihydroindenyl group,-   (16) a dihydrobenzofuryl group,-   (17) a benzodioxolyl group,-   (18) an indazolyl group,-   (19) a benzothiazolyl group,-   (20) an indolinyl group,-   (21) a thienopyridyl group,-   (22) a tetrahydrobenzazepinyl group,-   (23) a tetrahydrobenzodiazepinyl group,-   (24) a dihydrobenzodioxepinyl group,-   (25) a fluorenyl group,-   (26) a pyridazinyl group,-   (27) a tetrahydroquinolyl group,-   (28) a carbazolyl group,-   (29) a phenanthryl group,-   (30) a dihydroacenaphthylenyl group,-   (31) a pyrrolopyridyl group,-   (32) an anthryl group,-   (33) a benzodioxinyl group,-   (34) a pyrrolidinyl group,-   (35) a pyrazolyl group,-   (36) an oxadiazolyl group,-   (37) a pyrimidinyl group,-   (38) a tetrahydronaphthyl group,-   (39) a dihydroquinazolinyl group,-   (40) a benzoxazolyl group,-   (41) a thiazolyl group,-   (42) a quinazolinyl group,-   (43) a phthalazinyl group,-   (44) a pyrazinyl group, and-   (45) a chromenyl group, wherein-   these aromatic or heterocyclic groups may have one or more    substituent(s) selected from-   (1-1) a halogen atom,-   (1-2) a lower alkyl group,-   (1-3) a lower alkanoyl group,-   (1-4) a halogen-substituted lower alkyl group,-   (1-5) a halogen-substituted lower alkoxy group,-   (1-6) a cyano group,-   (1-7) a lower alkoxy group,-   (1-8) a lower alkylthio group,-   (1-9) an imidazolyl group,-   (1-10) a tri-lower alkylsilyl group,-   (1-11) an oxadiazolyl group which may have a lower alkyl group(s),-   (1-12) a pyrrolidinyl group which may have an oxo group(s),-   (1-13) a phenyl group which may have a lower alkoxy group(s),-   (1-14) a lower alkylamino-lower alkyl group,-   (1-15) an oxo group,-   (1-16) a pyrazolyl group which may have a lower alkyl group(s),-   (1-17) a thienyl group,-   (1-18) a furyl group,-   (1-19) a thiazolyl group which may have a lower alkyl group(s),-   (1-20) a lower alkylamino group,-   (1-21) a pyrimidyl group which may have a lower alkyl group(s),-   (1-22) a phenyl-lower alkenyl group,-   (1-23) a phenoxy group which may have a halogen atom(s),-   (1-24) a phenoxy-lower alkyl group,-   (1-25) a pyrrolidinyl-lower alkoxy group,-   (1-26) a lower alkylsulfamoyl group,-   (1-27) a pyridazinyloxy group which may have a lower alkyl group(s),-   (1-28) a phenyl-lower alkyl group,-   (1-29) a lower alkylamino-lower alkoxy group,-   (1-30) an imidazolyl-lower alkyl group,-   (1-31) a phenyl-lower alkoxy group,-   (1-32) a hydroxy group,-   (1-33) a lower alkoxycarbonyl group,-   (1-34) a hydroxy-lower alkyl group,-   (1-35) an oxazolyl group,-   (1-36) a piperidyl group,-   (1-37) a pyrrolyl group,-   (1-38) a morpholinyl-lower alkyl group,-   (1-39) a piperazinyl-lower alkyl group which may have a lower alkyl    group(s),-   (1-40) a piperidyl-lower alkyl group,-   (1-41) a pyrrolidinyl-lower alkyl group,-   (1-42) a morpholinyl group, and-   (1-43) a piperazinyl group which may have a lower alkyl group(s).-   Item 3. The heterocyclic compound represented by the general    formula (1) or a salt thereof according to item 2, wherein-   R⁴ represents any of-   (1) a phenyl group,-   (2) an indolyl group,-   (3) a benzothienyl group,-   (4) a naphthyl group,-   (5) a benzofuryl group,-   (6) a quinolyl group,-   (7) an isoquinolyl group,-   (8) a pyridyl group,-   (9) a thienyl group,-   (10) a dihydrobenzoxazinyl group,-   (11) a dihydrobenzodioxinyl group,-   (12) a dihydroquinolyl group,-   (13) a chromanyl group,-   (14) a quinoxalinyl group,-   (15) a dihydroindenyl group,-   (16) a dihydrobenzofuryl group,-   (17) a benzodioxolyl group,-   (18) an indazolyl group,-   (19) a benzothiazolyl group,-   (20) an indolinyl group,-   (21) a thienopyridyl group,-   (22) a tetrahydrobenzazepinyl group,-   (23) a tetrahydrobenzodiazepinyl group,-   (24) a dihydrobenzodioxepinyl group,-   (25) a fluorenyl group,-   (26) a pyridazinyl group,-   (27) a tetrahydroquinolyl group,-   (28) a carbazolyl group,-   (29) a phenanthryl group,-   (30) a dihydroacenaphthylenyl group,-   (31) a pyrrolopyridyl group,-   (32) an anthryl group,-   (33) a benzodioxinyl group,-   (34) a pyrrolidinyl group,-   (35) a pyrazolyl group,-   (36) an oxadiazolyl group,-   (37) a pyrimidinyl group,-   (38) a tetrahydronaphthyl group,-   (39) a dihydroquinazolinyl group,-   (40) a benzoxazolyl group,-   (41) a thiazolyl group,-   (42) a quinazolinyl group,-   (43) a phthalazinyl group,-   (44) a pyrazinyl group, and-   (45) a chromenyl group, wherein-   these aromatic or heterocyclic groups may have 1 to 4 substituent(s)    selected from-   (1-1) a halogen atom,-   (1-2) a lower alkyl group,-   (1-3) a lower alkanoyl group,-   (1-4) a halogen-substituted lower alkyl group,-   (1-5) a halogen-substituted lower alkoxy group,-   (1-6) a cyano group,-   (1-7) a lower alkoxy group,-   (1-8) a lower alkylthio group,-   (1-9) an imidazolyl group,-   (1-10) a tri-lower alkylsilyl group,-   (1-11) an oxadiazolyl group which may have 1 lower alkyl group,-   (1-12) a pyrrolidinyl group which may have 1 oxo group,-   (1-13) a phenyl group which may have 1 lower alkoxy group,-   (1-14) a lower alkylamino-lower alkyl group,-   (1-15) an oxo group,-   (1-16) a pyrazolyl group which may have 1 lower alkyl group,-   (1-17) a thienyl group,-   (1-18) a furyl group,-   (1-19) a thiazolyl group which may have 1 lower alkyl group,-   (1-20) a lower alkylamino group,-   (1-21) a pyrimidyl group which may have 1 lower alkyl group,-   (1-22) a phenyl-lower alkenyl group,-   (1-23) a phenoxy group which may have 1 halogen atom,-   (1-24) a phenoxy-lower alkyl group,-   (1-25) a pyrrolidinyl-lower alkoxy group,-   (1-26) a lower alkylsulfamoyl group,-   (1-27) a pyridazinyloxy group which may have 1 lower alkyl group,-   (1-28) a phenyl-lower alkyl group,-   (1-29) a lower alkylamino-lower alkoxy group,-   (1-30) an imidazolyl-lower alkyl group,-   (1-31) a phenyl-lower alkoxy group,-   (1-32) a hydroxy group,-   (1-33) a lower alkoxycarbonyl group,-   (1-34) a hydroxy-lower alkyl group,-   (1-35) an oxazolyl group,-   (1-36) a piperidyl group,-   (1-37) a pyrrolyl group,-   (1-38) a morpholinyl-lower alkyl group,-   (1-39) a piperazinyl-lower alkyl group which may have 1 lower alkyl    group,-   (1-40) a piperidyl-lower alkyl group,-   (1-41) a pyrrolidinyl-lower alkyl group,-   (1-42) a morpholinyl group, and-   (1-43) a piperazinyl group which may have 1 lower alkyl group.-   Item 4. The heterocyclic compound represented by the general    formula (1) or a salt thereof according to item 3, wherein-   m represents 2; 1 and n respectively represent an integer of 1; X    represents —CH₂—;-   R¹ represents hydrogen, a lower alkyl group, a hydroxy-lower alkyl    group, a benzyl group, or a tri-lower alkylsilyloxy-lower alkyl    group; and-   R⁴ represents any of-   (1) a phenyl group,-   (2) an indolyl group,-   (4) a naphthyl group,-   (5) a benzofuryl group, and-   (31) a pyrrolopyridyl group, wherein-   these aromatic or heterocyclic groups may have 1 to 4 substituent(s)    selected from-   (1-1) a halogen atom,-   (1-2) a lower alkyl group,-   (1-3) a lower alkanoyl group,-   (1-4) a halogen-substituted lower alkyl group,-   (1-5) a halogen-substituted lower alkoxy group,-   (1-6) a cyano group,-   (1-7) a lower alkoxy group,-   (1-8) a lower alkylthio group,-   (1-9) an imidazolyl group,-   (1-10) a tri-lower alkylsilyl group,-   (1-11) an oxadiazolyl group which may have 1 lower alkyl group,-   (1-12) a pyrrolidinyl group which may have 1 oxo group,-   (1-13) a phenyl group which may have 1 lower alkoxy group,-   (1-14) a lower alkylamino-lower alkyl group,-   (1-15) an oxo group,-   (1-16) a pyrazolyl group which may have 1 lower alkyl group,-   (1-17) a thienyl group,-   (1-18) a furyl group,-   (1-19) a thiazolyl group which may have 1 lower alkyl group,-   (1-20) a lower alkylamino group,-   (1-21) a pyrimidyl group which may have 1 lower alkyl group,-   (1-22) a phenyl-lower alkenyl group,-   (1-23) a phenoxy group which may have 1 halogen atom,-   (1-24) a phenoxy-lower alkyl group,-   (1-25) a pyrrolidinyl-lower alkoxy group,-   (1-26) a lower alkylsulfamoyl group,-   (1-27) a pyridazinyloxy group which may have 1 lower alkyl group,-   (1-28) a phenyl-lower alkyl group,-   (1-29) a lower alkylamino-lower alkoxy group,-   (1-30) an imidazolyl-lower alkyl group,-   (1-31) a phenyl-lower alkoxy group,-   (1-32) a hydroxy group,-   (1-34) a hydroxy-lower alkyl group,-   (1-35) an oxazolyl group,-   (1-36) a piperidyl group,-   (1-37) a pyrrolyl group,-   (1-38) a morpholinyl-lower alkyl group,-   (1-39) a piperazinyl-lower alkyl group which may have a lower alkyl    group(s),-   (1-40) a piperidyl-lower alkyl group,-   (1-41) a pyrrolidinyl-lower alkyl group,-   (1-42) a morpholinyl group, and-   (1-43) a piperazinyl group which may have 1 lower alkyl group.-   Item 5. The heterocyclic compound represented by the general    formula (1) or a salt thereof according to item 4, wherein-   R⁴ represents hydrogen;-   R² and R³, which are the same or different, each independently    represent a lower alkyl group; or-   R² and R³ are bonded to form a cyclo-C3-C8 alkyl group; and-   R⁴ represents any of-   (1) a phenyl group,-   (2) an indolyl group,-   (4) a naphthyl group,-   (5) a benzofuryl group, and-   (31) a pyrrolopyridyl group, wherein-   these aromatic or heterocyclic groups may have 1 to 2 substituent(s)    selected from-   (1-1) a halogen atom,-   (1-2) a lower alkyl group,-   (1-5) a halogen-substituted lower alkoxy group,-   (1-6) a cyano group, and-   (1-7) a lower alkoxy group.-   Item 6. The heterocyclic compound represented by the general    formula (1) or a salt thereof according to item 5, which is selected    from-   (4aS,8aR)-1-(4-chlorophenyl)-3,3-dimethyldecahydroquinoxaline,-   2-chloro-4-((4aS,8aS)-3,3-dimethyloctahydroquinoxalin-1(2H)-yl)benzonitrile,-   (4aS,8aR)-1-(3-chloro-4-fluorophenyl)-3,3-dimethyldecahydroquinoxaline,-   (4aS,8aR)-1-(7-fluorobenzofuran-4-yl)-3,3-dimethyldecahydroquinoxaline,-   5-((4aR,8aS)-3,3-dimethyloctahydroquinoxalin-1(2H)-yl)-1-methyl-1H-indole-2-carbonitrile,-   (4a′R,8a′S)-4′-(7-methoxybenzofuran-4-yl)octahydro-1′H-spiro[cyclobutane-1,2′-quinoxaline],-   (4aS,8aR)-1-(6,7-difluorobenzofuran-4-yl)-3,3-dimethyldecahydroquinoxaline,-   S-((4aS,8aS)-3,3-dimethyloctahydroquinoxalin-1(2H)-yl)-1H-indole-2-carbonitrile,-   (4aS,8aR)-1-(7-chloro-2,3-dihydro-1H-inden-4-yl)-3,3-dimethyldecahydroquinoxaline,-   6-((4aS,8aS)-3,3-dimethyloctahydroquinoxalin-1(2H)-yl)-2-naphthonitrile,-   (4aS,8aS)-3,3-dimethyl-1-(1H-pyrrolo[2,3-b]pyridin-4-yl)decahydroquinoxaline,    and,-   (4aS,8aS)-1-(4-(difluoromethoxy)-3-fluorophenyl)-3,3-dimethyldecahydroquinoxaline.-   Item 7. A pharmaceutical composition comprising a heterocyclic    compound represented by the general formula (1) or a salt thereof    according to item 1 as an active ingredient and a pharmaceutically    acceptable carrier.-   Item 8. A prophylactic and/or therapeutic agent for disorders caused    by reduced neurotransmission of serotonin, norepinephrine or    dopamine, comprising as an active ingredient a heterocyclic compound    of general formula (1) or a salt thereof according to item 1.-   Item 9. a prophylactic and/or therapeutic agent according to item 8,    wherein the disorder is selected from the group consisting of    depression, depression status caused by adjustment disorder, anxiety    caused by adjustment disorder, anxiety caused by various diseases,    generalized anxiety disorder, phobia, obsessive-compulsive disorder,    panic disorder, posttraumatic stress disorder, acute stress    disorder, hypochondria, dissociative amnesia, avoidant personality    disorder, body dysmorphic disorder, eating disorder, obesity,    chemical dependence, pain, fibromyalgia, Alzheimer's disease, memory    deficit, Parkinson's disease, restless leg syndrome, endocrine    disorder, vasospasm, cerebellar ataxia, gastrointestinal disorder,    negative syndrome of schizophrenia, premenstrual syndrome, stress    urinary incontinence, Tourette's disorder, attention deficit    hyperactivity disorder (ADHD), autism, Asperger syndrome, impulse    control disorder, trichotillomania, kleptomania, gambling disorder,    cluster headache, migraine, chronic paroxysmal hemicrania, chronic    fatigue syndrome, precocious ejaculation, male impotence,    narcolepsy, primary hypersomnia, cataplexy, sleep apnea syndrome and    headache.-   Item 10. a prophylactic and/or therapeutic agent according to item    9, wherein the depression is selected from the group consisting of    major depressive disorder; bipolar I disorder; bipolar II disorder;    mixed state; dysthymic disorder; rapid cycler; atypical depression;    seasonal affective disorder; postpartum depression; hypomelancholia;    recurrent brief depressive disorder; refractory depression; chronic    depression; double depression; alcohol-induced mood disorder; mixed    anxiety-depressive disorder; depression caused by various physical    diseases such as Cushing('s) syndrome, hypothyroidism,    hyperparathyroidism, Addison's disease, amenorrhea-galactorrhea    syndrome, Parkinson's disease, Alzheimer's disease, cerebrovascular    dementia, brain infarct, brain hemorrhage, subarachnoid hemorrhage,    diabetes millitus, virus infection, multiple sclerosis, chronic    fatigue syndrome, coronary artery disease, pain, cancer, etc.;    presenile depression; senile depression; depression in children and    adolescents; depression induced by drugs such as interferon, etc.-   Item 11. A prophylactic and/or therapeutic agent according to item    9, wherein the anxiety caused by various diseases is selected from    the group consisting of anxiety caused by head injury, brain    infection, inner ear impairment, cardiac failure, cardiac    dysrhythmia, hyperadrenalism, hyperthyroidism, asthma and chronic    obstructive pulmonary disease.-   Item 12. A prophylactic and/or therapeutic agent according to item    9, wherein the pain is selected from the group consisting of chronic    pain, psychogenic pain, neuropathic pain, phantom limb pain,    postherpetic neuralgia, traumatic cervical syndrome, spinal cord    injury pain, trigeminal neuralgia, diabetic neuropathy.-   Item 13. Use of a heterocyclic compound of the general formula (1)    or a salt thereof according to any one of items 1 to 6 as a drug.-   Item 14. Use of a heterocyclic compound of the general formula (1)    or a salt thereof according to any one of items 1 to 6 as a    serotonine reuptake inhibitor and/or a norepinephrine reuptake    inhibitor and/or a dopamine reuptake inhibitor.-   Item 15. A method for treating and/or preventing disorders caused by    reduced neurotransmission of serotonin, norephnephrine or dopamine,    comprising administering a heterocyclic compound of general    formula (1) or a salt thereof according to items 1 to 6 to a human    or an animal.-   Item 16. A process for producing a heterocyclic compound of general    formula (1):

or salts thereof, wherein m, l and n respectively represent an integerof 1 or 2; X, R¹, R², and R³ are defined in the above in item 1,

the process comprising reacting the compound represented by the generalformula;

wherein m, l and n respectively represent an integer of 1 or 2; X, R¹,R², and R³ are defined in the above in item 1 and the compoundrepresented by the general formula;R⁴—X₁

-   wherein R⁴ and X¹ are defined in the below.

Each group shown in the general formula is specifically as shown below.

The term “lower” means a group having 1 to 6 (preferably 1 to 4, morepreferably 1 to 3) carbon atoms, unless otherwise specified.

A heterocyclic ring group includes saturated or unsaturated monocyclicor polycyclic heterocyclic rings comprising at least one hetero atomsselected from an oxygen atom(s), a sulfur atom(s) and nitrogen atom(s).More preferably, it includes the following heterocyclic ring:

3 to 8 unsaturated-membered, preferably 5 or 6-membered heteromonocyclicring containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrroliny,imidazolyl, pyrazolyl, pyridyl groups and N-oxide thereof, pyrimidinyl,pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl,1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl groups etc.), tetrazolyl group(e.g., 1H-tetrazolyl, 2H-tetrazolyl groups, etc.), dihydrotriazinyl(e.g., 4,5-dihydro-1,2,4-triazinyl, 2,5-dihydro-1,2,4-triazinyl groups)groups, etc, can be mentioned. Preferably, imidazolyl, pyridazinyl,pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl groups, etc. can bementioned.

3 to 8-membered, preferably 5 or 6-membered unsaturated heteromonocyclicring containing 1 to 4 nitrogen atoms, for example, azetidinyl,pyrrolidinyl, imidazolidinyl, piperidinyl, pyrazolidinyl, pyperazinylgroups, etc. can be mentioned. Preferably, pyrrolidinyl group can bementioned.

7 to 12-membered partially saturated or unsaturated condensed heteroring group containing 1 to 5 nitrogen atoms, for example, indolyl,dihydroindolyl, (e.g., 2,3-dihydro-1H-dihydroindolyl group, etc.),isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl,dihydroisoquinolyl (e.g., 3,4-dihydro-1H-isoquinolyl group, etc.),tetrahydroquinolyl, tetrahydroisoquinolyl (e.g.,1,2,3,4-tetrahydro-1H-isoquinolyl, 5,6,7,8-tetrahydroisoquinolyl groups,etc.), carbostyril, dihydrocarbostyril (e.g., 3,4-dihydrocarbostyrilgroup, etc.), indazolyl, benzotriazolyl, tetrazolopyridyl,tetrazolopyridazinyl (e.g., tetrazolo[1,5-b]pyridazinyl group, etc.),dihydrotriazolopyridazinyl, imidazopyridyl (e.g., imidazo[1,2-a]pyridylgroup, etc.), naphthyridyl, cinnolinyl, quinoxalinyl, pyrazolopyridyl(e.g., pyrazolo[2,3-a]pyridyl group, etc.), pyrrolopyridyl, carbazolyl,Indolinyl, tetrahydrobenzodiazepinyl, tetrahydrobenzoazepinyl,quinazolinyl, phthalazinyl groups, etc. can be mentioned. Preferably,quinolyl, isoquinolyl, quinoxalinyl, indolyl, indazolyl, pyrrolopyridyl,tetrahydroquinolyl, carbazolyl, indolinyl, quinazolyl, phthalazinyl,tetrahydrobenzodiazepinyl, or tetrahydrobenzoazepinyl groups, etc. canbe mentioned.

3 to 8 membered, preferably 5 or 6 membered unsaturated heteromono ringcontaining 1 to 2 oxygen atoms, for example, furyl group, etc. can bementioned.

7 to 12-membered partially saturated or unsaturated condensed heteroring group containing 1 to 3 oxygen atoms, for example, benzofuryl,dihydrobenzofuryl (e.g., 2,3-dihydrobenzo[b]furyl group, etc.),chromanyl, benzodioxanyl (e.g., 1,4-benzodioxanyl group, etc.),dihydrobenzoxadinyl (e.g, 2,3-dihydrobenzo-1,4-oxadinyl), benzodioxolyl(e.g., benzo[1,3]dioxolyl group, etc.), benzodioxynyl,dihydrobenzodioxynyl, dihydrobenzodioxepinyl groups, etc. can bementioned. Preferably, benzofuryl, benzodioxynyl, benzodioxolyl,dihydrobenzofuryl, dihydrobenzodioxepinyl, dihydrobenzodioxsepinylyl,chromenyl, or chromanyl groups can be mentioned.

3 to 8-membered, preferably 5 or 6-membered unsaturated heteromonocyclicring containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, forexample, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl,1,3,4-oxadiazoyl, 1,2, S-oxadiazoyl groups, etc.) groups, etc. can bementioned. Preferably, oxazolyl, oxadiazolyl groups can be mentioned.

3 to 8-membered, preferably 5 or 6-membered saturated heteromonocyclicring containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, forexample, morpholinyl group, etc. can be mentioned.

7 to 12-membered partially saturated or unsaturated condensed heteroring containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, forexample, benzoxazoly, benzoxazdiazolyl, benzisoxazolyl, furopyridyl(e.g., furo[2,3-b]pyridyl, furo[3,2-c]pyridyl groups, etc.),dihydrobenzoxadinyl groups, etc. can be mentioned. Preferably,benzoxazolyl, dihydrobenzoxadinyl groups can be mentioned.

3 to 8-membered, preferably 5 or 6-membered unsaturated heteromonocyclicring containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, forexample, thiazolyl, 1,2-thiazolyl, thiazolynyl, thiadiazolyl (e.g.,1,2,4-tiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,2,3-thiadiazolyl groups, etc.) groups, etc. can be mentioned.Preferably, thiazolyl group can be mentioned.

3 to 8-membered, preferably, 5 or 6-membered saturated heteromonocyclicring containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, forexample, thiazolydinyl group, etc. can be mentioned.

3 to 8-membered, preferably, 5 or 6-membered unsaturatedheteromonocyclic ring containing 1 sulfur atom, for example, thienylgroup, etc. can be mentioned.

7 to 12-membered unsaturated condensed hetero ring containing 1 to 3sulfur atoms, for example, benzothienyl group (e.g., benzo[b]thienylgroup, etc.), etc. can be mentioned.

7 to 12-membered partially saturated or unsaturated condensed heteroring group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, forexample, benzothiazolyl, benzothadiazolyl, thienopyridyl (e.g.,thieno[2,3-b]pyridyl, thieno[2,3-c]pyridyl, thieno[3,2-c]pyridyl groups,etc.), imidazothiazolyl (e.g., imidazo[2,1-b]thiazolyl group, etc.),dihydroimidazothiazolyl (e.g., 2,3-dihydroimidazo[2,1-b]thiazolyl group,etc.), thienopyradinyl (e.g., thieno[2,3-b]pyradinyl group, etc.),groups, etc. can be mentioned. Preferably, thienopyridyl orbenzothiazolyl groups can be mentioned.

The above heterocyclic ring can be substituted by one or more optionalsubstituents.

As an aromatic ring, it includes, for example, C₆₋₁₄ aryl groups can bementioned. The preferable examples of the aryl groups are a phenyl,naphthyl, anthryl, phenanthryl, acenaphthylenyl, biphenyl, indenylgroups. Among them, phenyl, naphtyl, anthryl, phenanthryl groups arepreferable. The aryl groups can be partially saturated. As the partiallyunsaturated aryl groups are, for example, dihydroindenyl, fluorenyl,dihydroacenaphthylenyl, tetrahydronaphthyl groups. Here, the aboveheterocyclic rings can be substituted by one or more optionalsubstituents.

As a saturated hydrocarbon group, it includes, for example, lower alkyl,cyclo C3-C8 alkyl groups, etc.

As an unsaturated hydrocarbon group, it includes, for example, loweralkenyl, lower alkynyl, phenyl groups, etc.

A characteristic group is a generic term used to refer to groups binddirectly to a mother structure other than a carbon-carbon binding (atomsor atomic groups other than hydrogen), and —C≡N and >C═X (X=O, S, Se,Te, NH, NR). As the characteristic group, it includes, for example,carboxy, carbamoyl, cyano, hydroxy, amino groups, etc.

The optional substituents are the above heterocyclic rings, aromaticring groups, saturated hydrocarbon groups, unsaturated hydrocarbongroups, characteristic groups, etc. Preferably, the substituents (1-1)to (1-43) described in item 2 above can be mentioned.

Examples of the lower alkyl group can include linear or branched alkylgroups having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms),unless otherwise specified. More specifically, it includes methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl,n-pentyl, 1-ethylpropyl, isopentyl, neopentyl, n-hexyl,1,2,2-trimethylpropyl, 3,3-dimethylbutyl, 2-ethylbutyl, isohexyl, and3-methylpentyl groups, etc.

Examples of a lower alkoxy group can include linear or branched alkoxygroups having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms),unless otherwise specified. More specifically, it includes methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy,sec-butoxy, n-pentyloxy, 1-ethylpropoxy, isopentyloxy, neopentyloxy,n-hexyloxy, 1,2,2-trimethylpropoxy, 3,3-dimethylbutoxy, 2-ethylbutoxy,isohexyloxy, and 3-methylpentyloxy groups, etc.

Examples of a halogen atom include fluorine, chlorine, bromine, andiodine atoms, unless otherwise specified.

Examples of a halogen-substituted lower alkyl group can include thelower alkyl groups exemplified above which are substituted by 1 to 7(more preferably 1 to 3) halogen atoms, unless otherwise specified. Morespecifically, it includes fluoromethyl, difluoromethyl, trifluoromethyl,chloromethyl, dichloromethyl, trichloromethyl, bromomethyl,dibromomethyl, dichlorofluoromethyl, 2,2-difluoroethyl,2,2,2-trifluoroethyl, pentafluoroethyl, 2-fluoroethyl, 2-chloroethyl,3,3,3-trifluoropropyl, heptafluoropropyl, 2,2,3,3,3-pentafluoropropyl,heptafluoroisopropyl, 3-chloropropyl, 2-chloropropyl, 3-bromopropyl,4,4,4-trifluorobutyl, 4,4,4,3,3-pentafluorobutyl, 4-chlorobutyl,4-bromobutyl, 2-chlorobutyl, 5,5,5-trifluoropentyl, S-chloropentyl,6,6,6-trifluorohexyl, 6-chlorohexyl, and perfluorohexyl groups, etc.

Examples of a halogen-substituted lower alkoxy group can include thelower alkoxy groups exemplified above which are substituted by 1 to 7(preferably 1 to 3) halogen atoms, unless otherwise specified. Morespecifically, it includes fluoromethoxy, difluoromethoxy,trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy,bromomethoxy, dibromomethoxy, dichlorofluoromethoxy, 2,2-difluoroethoxy,2,2,2-trifluoroethoxy, pentafluoroethoxy, 2-fluoroethoxy,2-chloroethoxy, 3,3,3-trifluoropropoxy, heptafluoropropoxy,heptafluoroisopropoxy, 3-chloropropoxy, 2-chloropropoxy, 3-bromopropoxy,4,4,4-trifluorobutoxy, 4,4,4,3,3-pentafluorobutoxy, 4-chlorobutoxy,4-bromobutoxy, 2-chlorobutoxy, 5,5,5-trifluoropentyloxy,5-chloropentyloxy, 6,6,6-trifluorohexyloxy, 6-chlorohexyloxy, andperfluorohexyloxy groups, etc.

Examples of a cyclo-C3-C8 alkyl group include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups, etc.,unless otherwise specified.

Examples of a lower alkanoyl group can include linear or branchedalkanoyl groups having 1 to 6 carbon atoms (preferably 1 to 4 carbonatoms), unless otherwise specified. More specifically, it includesformyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl,tert-butylcarbonyl, and hexanoyl groups, etc.

Examples of a lower alkylthio group can include thio groups which aresubstituted by linear or branched alkyl groups having 1 to 6 carbonatoms (preferably 1 to 4 carbon atoms), unless otherwise specified. Morespecifically, it includes methylthio, ethylthio, n-propylthio,isopropylthio, n-butylthio, isobutylthio, tert-butylthio, sec-butylthio,n-pentylthio, 1-ethylpropylthio, isopentylthio, neopentylthio,n-hexylthio, 1,2,2-trimethylpropylthio, 3,3-dimethylbutylthio,2-ethylbutylthio, isohexylthio, and 3-methylpentylthio groups, etc.

Examples of a lower alkenyl group can include linear or branched alkenylgroups having 1 to 3 double bonds and 2 to 6 carbon atoms (preferably 2to 4 carbon atoms), unless otherwise specified, and the lower alkenylgroup encompasses both trans and cis forms. More specifically, itincludes vinyl, 1-propenyl, 2-propenyl, 1-methyl-1-propenyl,2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-butenyl, 1-butenyl,3-butenyl, 2-pentenyl, 1-pentenyl, 3-pentenyl, 4-pentenyl,1,3-butadienyl, 1,3-pentadienyl, 2-penten-4-yl, 2-hexenyl, 1-hexenyl,5-hexenyl, 3-hexenyl, 4-hexenyl, 3,3-dimethyl-1-propenyl,2-ethyl-1-propenyl, 1,3,5-hexatrienyl, 1,3-hexadienyl, and1,4-hexadienyl groups, etc.

Examples of a hydroxy-lower alkyl group can include the lower alkylgroups exemplified above (preferably, linear or branched alkyl groupshaving 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms)) whichhave 1 to 5, preferably 1 to 3 hydroxy groups, unless otherwisespecified. More specifically, it includes hydroxymethyl, 2-hydroxyethyl,2-hydroxypropyl, 1-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl,4-hydroxybutyl, 3,4-dihydroxybutyl, 1,1-dimethyl-2-hydroxyethyl,5-hydroxypentyl, 6-hydroxyhexyl, 3,3-dimethyl-3-hydroxypropyl,2-methyl-3-hydroxypropyl, 2,3,4-trihydroxybutyl, and perhydroxyhexylgroups, etc.

Examples of a lower alkylamino group can include amino groups having 1to 2 of the lower alkyl groups (preferably linear or branched alkylgroups having 1 to 6 (more preferably 1 to 4, even more preferably 1 to3) carbon atoms) exemplified above, unless otherwise specified. Morespecifically, it includes methylamino, dimethylamino, diethylamino, anddiisopropylamino groups, etc.

Examples of a lower alkylsulfamoyl group can include sulfamoyl groupshaving 1 to 2 of the lower alkyl groups (preferably linear or branchedalkyl groups having 1 to 6 (more preferably 1 to 4, even more preferably1 to 3) carbon atoms) exemplified above, unless otherwise specified.More specifically, it includes methylsulfamoyl, ethylsulfamoyl,dimethylsulfamoyl, diethylsulfamoyl, and ethylmethylsulfamoyl groups,etc.

A tri-lower alkylsilyl group can be exemplified by silyl groups whichare substituted by 3 linear or branched alkyl groups having 1 to 6carbon atoms, such as triisopropylsilyl, tert-butyldimethylsilyl,trimethylsilyl, n-butylethylmethylsilyl, tert-butyldipropylsilyl,n-pentyldiethylsilyl, and n-hexyl-n-propylmethylsilyl groups, etc.

Examples of a tri(lower alkyl)silyloxy-lower alkyl group can includetri(lower alkyl)silyloxy-lower alkyl groups whose lower alkyl moiety isany of the lower alkyl groups exemplified above (preferably, linear orbranched alkyl groups having 1 to 6 carbon atoms (more preferably 1 to 4carbon atoms)), unless otherwise specified. More specifically, itincludes trimethylsilyloxymethyl, 1-(or 2-)trimethylsilyloxyethyl, 1-(or2- or 3-)trimethylsilyloxypropyl, triethylsilyloxymethyl, 1-(or2-)triethylsilyloxyethyl, 1-(or 2- or 3-)triethylsilyloxypropyl,triisopropylsilyloxymethyl, 1-(or 2-)triisopropylsilyloxyethyl, and1-(or 2- or 3-)triisopropylsilyloxypropyl groups, etc.

Examples of a phenoxy-lower alkyl group can include the lower alkylgroups (preferably linear or branched alkyl groups having 1 to 6 (morepreferably 1 to 4, even more preferably 1 to 3) carbon atoms)exemplified above which have 1 to 3, preferably 1 phenoxy group, unlessotherwise specified. More specifically, it includes phenoxymethyl,1-phenoxyethyl, 2-phenoxyethyl, 3-phenoxypropyl, 2-phenoxypropyl,4-phenoxybutyl, 5-phenoxypentyl, 4-phenoxypentyl, 6-phenoxyhexyl,2-methyl-3-phenoxypropyl, and 1,1-dimethyl-2-phenoxyethyl groups, etc.

Examples of a phenyl-lower alkoxy group can include the lower alkoxygroups (preferably linear or branched alkoxy groups having 1 to 6 (morepreferably 1 to 4, even more preferably 1 to 3) carbon atoms)exemplified above which have 1 to 3, preferably 1 phenyl group, unlessotherwise specified. More specifically, it includes benzyloxy,2-phenylethoxy, 1-phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy,S-phenylpentyloxy, 6-phenylhexyloxy, 1,1-dimethyl-2-phenylethoxy, and2-methyl-3-phenylpropoxy groups, etc.

Examples of a phenyl-lower alkenyl group can include the lower alkenylgroups (preferably linear or branched alkenyl groups having 2 to 6 (morepreferably 2 to 4) carbon atoms) exemplified above which have 1 to 3,preferably 1 phenyl group, unless otherwise specified. Morespecifically, it includes styryl, 3-phenyl-2-propenyl (commonly calledcinnamyl), 4-phenyl-2-butenyl, 4-phenyl-3-butenyl, 5-phenyl-4-pentenyl,5-phenyl-3-pentenyl, 6-phenyl-5-hexenyl, 6-phenyl-4-hexenyl,6-phenyl-3-hexenyl, 4-phenyl-1,3-butadienyl, and6-phenyl-1,3,5-hexatrienyl groups, etc.

Examples of a lower alkylamino-lower alkyl group can include lower alkylgroups which have 1 to 2 of the lower alkylamino groups exemplifiedabove, unless otherwise specified. More specifically, it includesmethylaminomethyl, ethylaminomethyl, dimethylaminomethyl, 1-(or2-)dimethylaminoethyl, 1-(or 2- or 3-)dimethylaminopropyl,diisopropylaminomethyl, 1-(or 2-)diethylaminoethyl, andbis(dimethylamino)methyl groups, etc.

Examples of a lower alkylamino-lower alkoxy group can include loweralkoxy groups which have 1 to 2 of the lower alkylamino groupsexemplified above, unless otherwise specified. More specifically, itincludes methylaminomethoxy, ethylaminomethoxy, dimethylaminomethoxy,1-(or 2-)dimethylaminoethoxy, 1-(or 2- or 3-)dimethylaminopropoxy,diisopropylaminomethoxy, 1-(or 2-)diethylaminoethoxy, andbis(dimethylamino)methoxy groups, etc.

Examples of a dihydrobenzodioxinyl group include2,3-dihydrobenzo[b][1,4]dioxinyl, 3,4-dihydrobenzo[c][1,2]dioxinyl, and2,4-dihydrobenzo[d][1,3]dioxinyl groups, etc.

Examples of an imidazolyl-lower alkyl group can include the lower alkylgroups (preferably linear or branched alkyl groups having 1 to 6 (morepreferably 1 to 4) carbon atoms) exemplified above which have 1 to 3,preferably 1 imidazolyl group. More specifically, it includes 1-(or 2-or 4- or 5-)imidazolylmethyl, 1-(or 2-){1-(or 2- or 4- or5-)imidazolyl}ethyl, and 1-(or 2- or 3-){1-(or 2- or 4- or5-)imidazolyl}propyl groups, etc.

A dihydroindenyl group includes (1-, 2-, 4-, or 5-)-1,2-dihydroindenylgroups, etc.

A dihydroquinolyl group includes 1,2-dihydroquinolyl,3,4-dihydroquinolyl, 1,4-dihydroquinolyl, 4a,8a-dihydroquinolyl,5,6-dihydroquinolyl, 7,8-dihydroquinolyl, and 5,8-dihydroquinolylgroups, etc.

A fluorenyl group includes 1H-fluorenyl, 2H-fluorenyl, 3H-fluorenyl,4aH-fluorenyl, 5H-fluorenyl, 6H-fluorenyl, 7H-fluorenyl, 8H-fluorenyl,8aH-fluorenyl, and 9H-fluorenyl groups, etc.

A dihydrobenzofuryl group includes 2,3-dihydro-(2-, 3-, 4-, 5-, 6-, or7-)benzofuryl groups, etc.

A dihydrobenzoxazinyl group includes (2-, 3-, 4-, 5-, 6-, 7-, or8-)3,4-dihydro-2H-benzo[b][1.4]oxazinyl and (1-, 2-, 4-, 5-, 6-, 7-, or8-)2,4-dihydro-1H-benzo[d][1.3]oxazinyl groups, etc.

A tetrahydrobenzodiazepinyl group includes (1-, 2-, 3-, 4-, 5-, 6-, 7-,8-, or 9-) 2,3,4,5-tetrahydro-1H-benzo[b][1.4]diazepinyl and (1-, 2-,3-, 4-, 5-, 6-, 7-, 8-, or9-)2,3,4,5-tetrahydro-1H-benzo[e][1.4]diazepinyl groups, etc.

Examples of a tetrahydrobenzodiazepinyl group can include (1-, 2-, 3-,4-, 5-, 6-, 7-, 8-, or 9-)2,3,4,5-tetrahydro-1H-benzo[b][1.4]diazepinyland (1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, or9-)2,3,4,5-tetrahydro-1H-benzo[e][1.4]diazepinyl groups, etc.

A dihydrobenzodioxepinyl group includes3,4-dihydro-2H-1,5-benzodioxepinyl, 4,5-dihydro-3H-1,2-benzodioxepinyl,and 3,5-dihydro-2H-1,4-benzodioxepinyl groups, etc.

Examples of a pyrrolidinyl group which may have an oxo group(s) includepyrrolidinyl group which may have 1 to 2 (preferably 1) oxo groups,unless otherwise specified. More specifically, it includes (1-, 2-, or3-)pyrrolidinyl, (2- or 3-)oxo-1-pyrrolidinyl, (3-, 4-, or5-)oxo-2-pyrrolidinyl, and (2-, 4-, or 5-)oxo-3-pyrrolidinyl groups,etc.

Examples of an oxadiazolyl group which may have a lower alkyl group(s)can include oxadiazolyl group which may have 1 to 2 (preferably 1) ofthe lower alkyl groups exemplified above, unless otherwise specified.More specifically, it includes 5-methyl-1,3,4-oxadiazolyl,5-ethyl-1,3,4-oxadiazolyl, 5-propyl-1,3,4-oxadiazolyl,5-butyl-1,3,4-oxadiazolyl, 5-pentyl-1,3,4-oxadiazolyl, and5-hexyl-1,3,4-oxadiazolyl groups, etc.

Examples of a pyrazolyl group which may have a lower alkyl group(s) caninclude pyrazolyl group which may have 1 to 2 (preferably 1) of thelower alkyl groups exemplified above, unless otherwise specified. Morespecifically, it includes 1-methyl-1H-pyrazolyl, 1-ethyl-1H-pyrazolyl,1-propyl-1H-pyrazolyl, 1-isopropyl-1H-pyrazolyl, 1-butyl-1H-pyrazolyl,1-tert-butyl-1H-pyrazolyl, and 1,3-dimethyl-1H-pyrazolyl groups, etc.

Examples of a thiazolyl group which may have a lower alkyl group(s) caninclude thiazolyl group which may have 1 to 2 (preferably 1) of thelower alkyl groups exemplified above, unless otherwise specified. Morespecifically, it includes 2-methylthiazolyl, 2-ethylthiazolyl,2-propylthiazolyl, 2-isopropylthiazolyl, 2-butylthiazolyl,2-tert-butylthiazolyl, and 2,5-dimethylthiazolyl groups, etc.

Examples of a pyrimidyl group which may have a lower alkyl group(s) caninclude pyrimidyl group which may have 1 to 2 (preferably 1) of thelower alkyl groups exemplified above, unless otherwise specified. Morespecifically, it includes 2-methylpyrimidyl, 2-ethylpyrimidyl,2-propylpyrimidyl, 2-isopropylpyrimidyl, 2-butylpyrimidyl,2-tert-butylpyrimidyl, and 2,4-dimethylpyrimidyl groups, etc.

Examples of a pyridazinyl group which may have a lower alkyl group(s)can include pyridazinyl group which may have 1 to 2 (preferably 1) ofthe lower alkyl groups exemplified above, unless otherwise specified.More specifically, it includes 3-methylpyridazinyl, 3-ethylpyridazinyl,3-propylpyridazinyl, 3-isopropylpyridazinyl, 3-butylpyridazinyl,3-tert-butylpyridazinyl, and 3,4-dimethylpyridazinyl groups, etc.

Examples of a pyridazinyloxy group which may have a lower alkyl group(s)can include oxy group which is substituted by pyridazinyl which may have1 to 2 (preferably 1) of the lower alkyl groups exemplified above,unless otherwise specified. More specifically, it includes6-methylpyridazinyl-3-yloxy and 4-methylpyridazinyl-3-yloxy groups, etc.

Examples of a pyrrolidinyl-lower alkoxy group can include lower alkoxygroups (preferably linear or branched alkoxy groups having 1 to 6 (morepreferably 1 to 4, even more preferably 1 to 3) carbon atoms)exemplified above which have 1 to 3, preferably 1 pyrrolidinyl group,unless otherwise specified. Specific examples thereof include (1-, 2-,or 3-) pyrrolidinylmethoxy, 2-[(1-, 2-, or 3-)pyrrolidinyl]ethoxy,1-[(1-, 2-, or 3-)pyrrolidinyl]ethoxy, 3-[(1-, 2-, or3-)pyrrolidinyl]propoxy, 4-[(1-, 2-, or 3-)pyrrolidinyl]butoxy, 5-[(1-,2-, or 3-) pyrrolidinyl]pentyloxy, 6-[(1-, 2-, or3-)pyrrolidinyl]hexyloxy, 1,1-dimethyl-2-[(1-, 2-, or 3-)pyrrolidinyl]ethoxy, and 2-methyl-3-[(1-, 2-, or 3-)pyrrolidinyl]propoxygroups, etc.

Examples of a protecting group include protecting groups routinely used,such as substituted or unsubstituted lower alkanoyl [e.g., formyl,acetyl, propionyl, and trifluoroacetyl], phthaloyl, lower alkoxycarbonyl[e.g., tertiary butoxycarbonyl and tertiary amyloxycarbonyl],substituted or unsubstituted aralkyloxycarbonyl [e.g., benzyloxycarbonyland p-nitrobenzyloxycarbonyl], 9-fluorenylmethoxycarbonyl, substitutedor unsubstituted arenesulfonyl [e.g., benzenesulfonyl and tosyl],nitrophenylsulfenyl, aralkyl [e.g., trityl and benzyl], and loweralkylsilyl groups [e.g., triisopropylsilyl].

Examples of a phenyl-lower alkyl group can include the lower alkylgroups (preferably linear or branched alkyl groups having 1 to 6 (morepreferably 1 to 4 carbon atoms) exemplified above which have 1 to 3,preferably 1 phenyl group, unless otherwise specified. Morespecifically, it includes benzyl, phenethyl, 3-phenylpropyl, benzhydryl,trityl, 4-phenylbutyl, 5-phenylpentyl, and 6-phenylhexyl groups, etc.

Examples of a morpholinyl-lower alkyl group can include the lower alkylgroups (preferably linear or branched alkyl groups having 1 to 6 carbonatoms) exemplified above which have 1 to 2 (preferably 1) morpholinylgroups, unless otherwise specified. More specifically, it includes2-morpholinyl methyl, 3-morpholinyl methyl, 4-morpholinyl methyl,2-(2-morpholinyl)ethyl, 2-(3-morpholinyl)ethyl, 2-(4-morpholinyl)ethyl),1-(2-morpholinyl)ethyl, 1-(3-morpholinyl)ethyl, 1-(4-morpholinyl)ethyl,3-(2-morpholinyl)propyl, 3-(3-morpholinyl)propyl,3-(4-morpholinyl)propyl, 4-(2-morpholinyl)butyl, 4-(3-morpholinyl)butyl,4-(4-morpholinyl)butyl, 5-(2-morpholinyl)pentyl,5-(3-morpholinyl)pentyl, 5-(4-morpholinyl)pentyl,6-(2-morpholinyl)hexyl, 6-(3-morpholinyl)hexyl, 6-(4-morpholinyl)hexyl,3-methyl-3-(2-morpholinyl)propyl, 3-methyl-3-(3-morpholinyl)propyl,1,1-dimethyl-2-(2-morpholinyl)ethyl,1,1-dimethyl-2-(3-morpholinyl)ethyl, and1,1-dimethyl-2-(4-morpholinyl)ethyl groups, etc.

Examples of a pyrrolidinyl-lower alkyl group can include the lower alkylgroups exemplified above which have 1 to 3 (preferably 1) pyrrolidinylgroups, unless otherwise specified. More specifically, it includes (1-,2-, or 3-) pyrrolidinylmethyl, 2-[(1-, 2- or 3-) pyrrolidinyl]ethyl,1-[(1-, 2- or 3-)]pyrrolidinyl]ethyl, 3-[(1-, 2- or3-)]pyrrolidinyl]propyl, 4-[(1-, 2- or 3-)]pyrrolidinyl]butyl, 5-[(1-,2- or 3-)]pyrrolidinyl]pentyl, 6-[(1-, 2- or 3-)]pyrrolidinyl]hexyl,1,1-dimethyl-2-[(1-, 2- or 3-)]pyrrolidinyl]ethyl, and 2-methyl-3-[(1-,2- or 3-)]pyrrolidinyl]propyl groups, etc.

Examples of a piperidyl-lower alkyl group can include the lower alkylgroups (preferably linear or branched alkyl groups having 1 to 6 carbonatoms) exemplified above which have 1 to 2 (preferably 1) piperidylgroups, unless otherwise specified. More specifically, it includes (1-,2-, 3- or 4-) piperidylmethyl, 2-[(1-, 2-, 3- or 4-)piperidyl]ethyl,1-[(1-, 2-, 3- or 4-)piperidyl]ethyl, 3-[(1-, 2-, 3- or4-)piperidyl]propyl, 4-[(1-, 2-, 3- or 4-)piperidyl]butyl,1,1-dimethyl-2-[(1-, 2-, 3- or 4-)piperidyl]ethyl, 5-[(1-, 2-, 3- or4-)piperidyl]pentyl, 6-[(1-, 2-, 3- or 4-)piperidyl]hexyl, 1-[(l-, 2-,3- or 4-)piperidyl]isopropyl, and 2-methyl-3-[(1-, 2-, 3- or4-)piperidyl]propyl groups, etc.

Examples of a lower alkoxycarbonyl group can include linear or branchedalkoxy groups having preferably 1 to 6 carbon atoms and having a loweralkoxycarbonyl moiety as exemplified above. More specifically, itincludes methoxycarbonyl, ethoxycarbonyl, n-propxycarbonyl,isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl,tert-butoxycarbonyl, sec-butoxycarbonyl, n-pentyloxycarbonyl,neopentyloxycarbonyl, n-hexyloxycarbonyl, isohexyloxycarbonyl,3-methylpentyloxycarbonyl groups, etc.

Examples of a piperazinyl group which may have a lower alkyl group(s)include piperazinyl groups which may have 1 to 2 (preferably 1) loweralkyl groups, unless otherwise specified. More specifically, it includes2-methylpiperazinyl, 4-methylpiperazinyl, 2-ethylpiperazinyl,2-propylpiperazinyl, 2-isopropylpiperazinyl, 2-butylpiperazinyl,2-tertbutylpiperazinyl, and 2,4-dimethylpiperazinyl groups, etc.

Examples of a piperazinyl-lower alkyl group which may have a lower alkylgroup(s) include piperazinyl groups exemplified above which may have 1to 2 (preferably 1) lower alkyl groups, unless otherwise specified. Morespecifically, it includes 1-(4-methylpiperazinyl)methyl, 1-(2-methylpiperazinyl)methyl, 2-(1-methyl piperazinyl)ethyl, 3-(1-methylpiperazinyl)propyl, 4-(1-methyl piperazinyl)butyl groups, etc.

Examples of a phenyl group which may have a lower alkoxy group(s)include phenyl groups exemplified above which may have 1 to 2(preferably 1) lower alkoxy groups, unless otherwise specified. Morespecifically, it includes 4-methoxyphenyl, 4-ethoxyphenyl,4-propoxyphenyl, 4-isopropylphenyl, 4-butoxyphenyl, 4-tert butoxyphenylgroups, etc. can be mentioned As a phenoxy group exemplified above whichmay have a halogen atom(s) include phenoxy groups which may have 1 to 4(preferably 1) halogen atoms, unless otherwise specified. Morespecifically, it includes 4-fluorophenoxy, 3,4-difluorophenoxy,3,4,5-trifluorophenoxy, and 3-chloro-4,5-difluorophenoxy groups, etc.

A tetrahydroquinolyl group includes, for example,1,2,3,4-tetrahydroquinolyl, 5,6,7,8-tetrahydroquinolyl,4a,5,8,8a-tetrahydroquinolyl, 3,4,4a,8a-tetrahydroquinolyl,4a,5,8,8a-tetrahydroquinolyl, and 4a,5,6,7-tetrahydroquinolyl groups,etc.

A dihydroacenaphthylenyl group includes, for example,1,2-dihydroacenaphthylenyl, 2a¹, 3-dihydroacenaphthylenyl,5,6-dihydroacenaphthylenyl, 3,7-dihydroacenaphthylenyl, 2a¹,6-dihydroacenaphthylenyl, 1,2a¹-dihydroacenaphthylenyl, and6,8a-dihydroacenaphthylenyl groups, etc. More preferably, it is1,2-dihydroacenaphthylenyl group can be mentioned.

A tetrahydronaphthyl group includes, for example,1,2,3,4-tetrahydronaphthyl, 1,2,3,5-tetrahydronaphthyl, and5,6,7,8-tetrahydronaphthyl, 2,3,7,8-tetrahydronaphthyl groups, etc. canbe mentioned.

A dihydroquinazolinyl group includes, for example,1,2-dihydroquinazolinyl, 3,4-dihydroquinazolinyl,4a,5-dihydroquinazolinyl, 5,6-dihydroquinazolinyl,6,7-dihydroquinazolinyl, 7,8-dihydroquinazolinyl,8,8a-dihydroquinazolinyl, and 4a,8a-dihydroquinazolinyl groups, etc. canbe mentioned.

The heterocyclic compound represented by the general formula (1) can beproduced by various methods. As an example, the heterocyclic compoundrepresented by the general formula (1) is produced by methodsrepresented by the reaction formulas shown below.

Reaction Formula-1

wherein R¹, R², R³, R⁴, X, l, m, and n are defined as above, and X₁represents a leaving group.

In the general formula (3), the leaving group represented by X₁ can beexemplified by halogen atoms, lower alkanesulfonyloxy groups,arylsulfonyloxy groups, aralkylsulfonyloxy groups,trihalomethanesulfonyloxy groups, sulfonio groups, and toluenesulfoxygroups. Preferable examples of the leaving groups for the presentreaction include halogen atoms.

Examples of the halogen atoms represented by X₁ can include fluorine,chlorine, bromine, and iodine atoms.

The lower alkanesulfonyloxy groups represented by X₁ can be exemplifiedspecifically by linear or branched alkanesulfonyloxy groups having 1 to6 carbon atoms, such as methanesulfonyloxy, ethanesulfonyloxy,n-propanesulfonyloxy, isopropanesulfonyloxy, n-butanesulfonyloxy,tert-butanesulfonyloxy, n-pentanesulfonyloxy, and n-hexanesulfonyloxygroups.

Examples of the arylsulfonyloxy groups represented by X₁ can include:phenylsulfonyloxy groups which may have 1 to 3 groups selected from thegroup consisting of linear or branched alkyl groups having 1 to 6 carbonatoms, linear or branched alkoxy groups having 1 to 6 carbon atoms,nitro groups, and halogen atoms as substituents on the phenyl ring; andnaphthylsulfonyloxy groups. The phenylsulfonyloxy groups which may havethe substituents can be exemplified specifically by phenylsulfonyloxy,4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy,4-nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy,2-nitrophenylsulfonyloxy, and 3-chlorophenylsulfonyloxy groups. Thenaphthylsulfonyloxy groups can be exemplified specifically byα-naphthylsulfonyloxy and β-naphthylsulfonyloxy groups.

Examples of the aralkylsulfonyloxy groups represented by X₁ can include:linear or branched alkanesulfonyloxy groups having 1 to 6 carbon atoms,which are substituted by a phenyl group which may have 1 to 3 groupsselected from the group consisting of linear or branched alkyl groupshaving 1 to 6 carbon atoms, linear or branched alkoxy groups having 1 to6 carbon atoms, nitro groups, and halogen atoms as substituents on thephenyl ring; and linear or branched alkanesulfonyloxy groups having 1 to6 carbon atoms, which are substituted by a naphthyl group. Thealkanesulfonyloxy groups which are substituted by the phenyl group canbe exemplified specifically by benzylsulfonyloxy,2-phenylethylsulfonyloxy, 4-phenylbutylsulfonyloxy,4-methylbenzylsulfonyloxy, 2-methylbenzylsulfonyloxy,4-nitrobenzylsulfonyloxy, 4-methoxybenzylsulfonyloxy, and3-chlorobenzylsulfonyloxy. The alkanesulfonyloxy groups which aresubstituted by the naphthyl group can be exemplified specifically byα-naphthylmethylsulfonyloxy and β-naphthylmethylsulfonyloxy groups.

The perhaloalkanesulfonyloxy groups represented by X₁ can be exemplifiedspecifically by trifluoromethanesulfonyloxy groups.

Examples of the sulfonio groups represented by X₁ can specificallyinclude dimethylsulfonio, diethylsulfonio, dipropylsulfonio,di-(2-cyanoethyl)sulfonio, di-(2-nitroethyl)sulfonio,di-(aminoethyl)sulfonio, di-(2-methylaminoethyl)sulfonio,di-(2-dimethylaminoethyl)sulfonio, di-(2-hydroxyethyl)sulfonio,di-(3-hydroxypropyl)sulfonio, di-(2-methoxyethyl)sulfonio,di-(2-carbamoylethyl)sulfonio, di-(2-carbamoylethyl)sulfonio,di-(2-carboxyethyl)sulfonio, and di-(2-methoxycarbonylethyl)sulfonio,and diphenylsulfonio groups.

A compound represented by the general formula (2) and the compoundrepresented by the general formula (3) can be reacted in the presence ofa palladium catalyst in the presence or absence of a basic compoundwithout or in an inert solvent to thereby produce the compound (1).

Examples of the inert solvent can include, for example: water; ethersolvents such as dioxane, tetrahydrofuran, diethyl ether,1,2-dimethoxyethane, diethylene glycol dimethyl ether, and ethyleneglycol dimethyl ether; aromatic hydrocarbon solvents such as benzene,toluene, and xylene; lower alcohol solvents such as methanol, ethanol,and isopropanol; ketone solvents such as acetone and methyl ethylketone; and polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), hexamethylphosphoric triamide, and acetonitrile. Theseinert solvents are used alone or as a mixture of two or more of them.

The palladium compound used in the present reaction is not particularlylimited. Examples thereof include: tetravalent palladium catalysts suchas sodium hexachloropalladium (IV) acid tetrahydrate and potassiumhexachloropalladium (IV) acid; divalent palladium catalysts such aspalladium (II) chloride, palladium (II) bromide, palladium (II) acetate,palladium (II) acetylacetonate, dichlorobis(benzonitrile)palladium (II),dichlorobis(acetonitrile)palladium (II),dichlorobis(triphenylphosphine)palladium (II), dichlorotetraamminepalladium (11), dichloro(cycloocta-1,5-diene)palladium (II), andpalladium (II) trifluoroacetate1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II)-dichloromethane complex; and zerovalent palladium catalysts such astris(dibenzylideneacetone)dipalladium (0),tris(dibenzylideneacetone)dipalladium (0)-chloroform complex, andtetrakis(triphenylphosphine)palladium (0). These palladium compounds areused alone or as a mixture of two or more of them.

In the present reaction, the amount of the palladium catalyst used isnot particularly limited and usually ranges from 0.000001 to 20 mol interms of palladium with respect to 1 mol of the compound of the generalformula (2). More preferably, the amount of the palladium compound usedranges from 0.0001 to 5 mol in terms of palladium with respect to 1 molof the compound of the general formula (2).

The present reaction proceeds advantageously in the presence of anappropriate ligand. For example,2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP),tri-o-tolylphosphine, bis(diphenylphosphino)ferrocene,triphenylphosphine, tri-t-butylphosphine, tricyclohexylphosphine, and9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (XANTPHOS) can be usedas the ligand for the palladium catalyst. These ligands are used aloneor as a mixture of two or more of them.

Furthermore, in the present invention, the tertiary phosphine may beprepared in a complex form in advance and added thereto. Examples of thecomplex can include tri-t-butylphosphonium tetrafluoroborate andtri-t-butylphosphonium tetraphenylborate.

The ratio between the palladium catalyst and the ligand used is notparticularly limited. The amount of the ligand used is approximately 0.1to 100 mol, preferably approximately 0.5 to 15 mol, with respect to 1mol of the palladium catalyst.

Inorganic and organic bases known in the art can be used widely as thebasic compound.

Examples of the inorganic bases can include: alkali metal hydroxidessuch as sodium hydroxide, potassium hydroxide, cesium hydroxide, andlithium hydroxide; alkali metal carbonates such as sodium carbonate,potassium carbonate, cesium carbonate, and lithium carbonate; alkalimetal bicarbonates such as lithium bicarbonate, sodium bicarbonate, andpotassium bicarbonate; alkali metals such as sodium and potassium;phosphates such as sodium phosphate and potassium phosphate; amides suchas sodium amide; and alkali metal hydrides such as sodium hydride andpotassium hydride.

Examples of the organic bases can include: alkali metal lower alkoxidessuch as sodium methoxide, sodium ethoxide, sodium t-butoxide, potassiummethoxide, potassium ethoxide, and potassium t-butoxide; and amines suchas triethylamine, tripropylamine, pyridine, quinoline, piperidine,imidazole, N-ethyldiisopropylamine, dimethylaminopyridine,trimethylamine, dimethylaniline, N-methylmorpholine,1,5-diazabicyclo[4.3.0]non-5-ene (DBN),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and1,4-diazabicyclo[2.2.2]octane (DABCO).

These basic compounds are used alone or as a mixture of two or more ofthem. More preferable examples of the basic compound used in the presentreaction include alkali metal carbonates such as sodium carbonate,potassium carbonate, cesium carbonate, and lithium carbonate, and sodiumt-butoxide.

The amount of the basic compound used is usually 0.5 to 10 mol,preferably 0.5 to 6 mol, with respect to 1 mol of the compound of thegeneral formula (2).

The ratio between the compound of the general formula (2) and thecompound of the general formula (3) used in the Reaction Formula-1 maybe at least 1 mol, preferably approximately 1 to 5 mol of the lattercompound with respect to 1 mol of the former compound.

The reaction can be performed in an atmosphere of inert gas such asnitrogen or argon under the atmospheric pressure or can be performedunder increased pressure.

The present reaction is usually performed under temperature conditionsinvolving room temperature to 200° C., preferably room temperature to150° C., and generally completed in approximately 1 to 30 hours. It isalso achieved by heating at 100 to 200° C. for 5 minutes to 1 hour usinga microwave reactor.

After the completion of the reaction, the reaction product can betreated by a standard method to obtain the compound of interest.

The compound represented by the general formula (2) used as a startingmaterial in the Reaction Formula-1 is produced from compounds known inthe art, for example, by methods represented by Reaction Formulas-3 and4 shown below. The compound represented by the general formula (3) is aneasily obtainable compound known in the art or a compound easilyproduced by a method known in the art.

Reaction Formula-2

wherein R², R³, R⁴, X, l, m, and n are defined as above; and R^(1a)represents a protecting group.

Examples of the protecting group include the protecting groupsexemplified 6 above.

The compound represented by the general formula (1b) can be produced bysubjecting a compound represented by the general formula (1a) to theelimination reaction of the protecting group.

A method routinely used such as hydrolysis or hydrogenolysis can beapplied to the elimination reaction of the protecting group.

The present reaction is usually performed in a solvent routinely usedthat does not adversely affect the reaction. Examples of the solventinclude: water; alcohol solvents such as methanol, ethanol, isopropanol,n-butanol, trifluoroethanol, and ethylene glycol, ketone solvents suchas acetone and methyl ethyl ketone; ether solvents such astetrahydrofuran, dioxane, diethyl ether, dimethoxyethane, and diglyme;ester solvents such as methyl acetate and ethyl acetate; aprotic polarsolvents such as acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, and N-methylpyrrolidone; halogenated hydrocarbon solventssuch as methylene chloride and ethylene chloride; and other organicsolvents.

(i) Hydrolysis:

The hydrolysis is preferably performed in the presence of a base or anacid (including Lewis acids).

Inorganic and organic bases known in the art can be used widely as thebase. Preferable examples of the inorganic bases include alkali metals(e.g., sodium and potassium), alkaline earth metals (e.g., magnesium andcalcium), and hydrides, carbonates, or bicarbonates thereof. Preferableexamples of the organic bases include trialkylamines (e.g.,trimethylamine and triethylamine), picoline, and1,5-diazabicyclo[4.3.0]non-5-ene.

Organic and inorganic acids known in the art can be used widely as theacid. Preferable examples of the organic acids include: fatty acids suchas formic acid, acetic acid, and propionic acid; and trihaloacetic acidssuch as trichloroacetic acid and trifluoroacetic acid. Preferableexamples of the inorganic acids include hydrochloric acid, hydrobromicacid, sulfuric acid, hydrogen chloride, and hydrogen bromide. Examplesof the Lewis acids include boron trifluoride-ether complexes, borontribromide, aluminum chloride, and ferric chloride.

When trihaloacetic acid or Lewis acid is used as the acid, the reactionis preferably performed in the presence of a cation scavenger (e.g.,anisole and phenol).

The amount of the base or the acid used is not particularly limited aslong as it is an amount necessary for hydrolysis.

The reaction temperature is usually 0 to 120° C., preferably roomtemperature to 100° C., more preferably room temperature to 80° C. Thereaction time is usually 30 minutes to 24 hours, preferably 30 minutesto 12 hours, more preferably 1 to 8 hours.

(ii) Hydrogenolysis:

Hydrogenolysis methods known in the art can be applied widely to thehydrogenolysis. Examples of such hydrogenolysis methods include chemicalreduction and catalytic reduction.

Preferable reducing agents used in chemical reduction are thecombinations of hydrides (e.g., hydrogen iodide, hydrogen sulfide,lithium aluminum hydride, sodium borohydride, and sodiumcyanoborohydride), metals (e.g., tin, zinc, and iron), or metalcompounds (e.g., chromium chloride and chromium acetate) with organic orinorganic acids (e.g., formic acid, acetic acid, propionic acid,trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, andhydrobromic acid).

Preferable catalysts used in catalytic reduction are platinum catalysts(e.g., platinum plates, platinum sponge, platinum black, colloidalplatinum, platinum oxide, and platinum wires), palladium catalysts(e.g., palladium sponge, palladium black, palladium oxide,palladium-carbon, palladium/barium sulfate, and palladium/bariumcarbonate), nickel catalysts (e.g., reduced nickel, nickel oxide, andRaney nickel), cobalt catalysts (e.g., reduced cobalt and Raney cobalt),iron catalysts (e.g., reduced iron), etc.

When these acids used in chemical reduction are in a liquid state, theycan also be used as solvents.

The amount of the reducing agent used in chemical reduction or thecatalyst used in catalytic reduction is not particularly limited and maybe an amount usually used.

The reaction of the present invention can be performed in an atmosphereof inert gas such as nitrogen or argon under the atmospheric pressure orcan be performed under increased pressure.

The reaction temperature is usually 0 to 120° C., preferably roomtemperature to 100° C., more preferably room temperature to 80° C. Thereaction time is usually 30 minutes to 24 hours, preferably 30 minutesto 10 hours, more preferably 30 minutes to 4 hours.

After the completion of the reaction, the reaction product can betreated by a standard method to obtain the compound of the generalformula (1b) of interest.

The deprotection reaction of the protecting group is not limited to thereaction conditions described above. For example, reaction described inT. W. Green, P. G. M. Wuts, “Protective Groups in Organic Synthesis”,4th ed., or John Wiley & Sons; New York, 1991, P 309 can also be appliedto the present reaction step.

The compound represented by the general formula (2) is a novel compound,which is useful as an intermediate for the compound represented by thegeneral formula (1), as described above.

The compound of the general formula (2) is produced according to, forexample, Reaction Formulas-3, 4, or 5 shown below.

Hereinafter, each reaction formula will be described.

Reaction Formula-3

wherein R¹, R², R³, X, l, m, and n are defined as above.

The compound represented by the general formula (2a) is produced bysubjecting a compound represented by the general formula (4) and acompound represented by the general formula (5) to cyclization reactionto form a compound represented by the general formula (6) (Step A),which is then reduced (Step B).

Step A

The reaction between the compound represented by the general formula (4)and the compound represented by the general formula (5) can be performedin the presence or absence of a base without or in an inert solvent.

Examples of the inert solvent can include, for example: water; etherssuch as dioxane, tetrahydrofuran, diethyl ether, diethylene glycoldimethyl ether, and ethylene glycol dimethyl ether; aromatichydrocarbons such as benzene, toluene, and xylene; lower alcohols suchas methanol, ethanol, and isopropanol; ketones such as acetone andmethyl ethyl ketone; and polar solvents such as N,N-dimethylformamide(DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide, andacetonitrile.

Basic compounds known in the art can be used widely. Examples thereofcan include: alkali metal hydroxides such as sodium hydroxide, potassiumhydroxide, cesium hydroxide, and lithium hydroxide; alkali metalcarbonates such as sodium carbonate, potassium carbonate, cesiumcarbonate, and lithium carbonate; alkali metals such as sodium andpotassium; other inorganic bases such as sodium amide, sodium hydride,and potassium hydride; alkali metal alcoholates such as sodiummethoxide, sodium ethoxide, potassium methoxide, and potassium ethoxide;and other organic bases such as triethylamine, tripropylamine, pyridine,quinoline, piperidine, imidazole, N-ethyldiisopropylamine,dimethylaminopyridine, trimethylamine, dimethylaniline,N-methylmorpholine, 1,5-diazacyclo[4.3.0]non-5-ene (DBN),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and1,4-diazabicyclo[2.2.2]octane (DABCO).

These basic compounds are used alone or as a mixture of two or more ofthem.

The amount of the basic compound used is usually 0.5 to 10 mol,preferably 0.5 to 6 mol, with respect to the compound of the generalformula (4).

The reaction can be performed by adding, if necessary, alkali metaliodide (e.g., potassium iodide and sodium iodide) as a reactionpromoter.

The ratio between the compound of the general formula (4) and thecompound of the general formula (5) used in the reaction formula may beusually at least 0.5 mol, preferably approximately 0.5 to 5 mol of thelatter compound with respect to 1 mol of the former compound.

The reaction of the present invention can be performed in an atmosphereof inert gas such as nitrogen or argon under the atmospheric pressure orcan be performed under increased pressure.

The reaction is usually performed under temperature conditions involving0° C. to 200° C., preferably room temperature to 150° C., and generallycompleted in approximately 1 to 30 hours.

The compound of the general formula (4) and the compound of the generalformula (5) used as starting materials in the Step A are easilyobtainable compounds known in the art or compounds easily produced by amethod known in the art.

Step B

The compound represented by the general formula (2a) can be produced bysubjecting the compound represented by the general formula (6) toreduction reaction without or in an inert solvent.

Examples of such reduction methods include chemical reduction andcatalytic reduction.

Examples of the inert solvent can include: water; ethers such asdioxane, tetrahydrofuran, diethyl ether, diethylene glycol methyl ether,and ethylene glycol dimethyl ether; aromatic hydrocarbons such asbenzene, toluene, and xylene, lower alcohols such as methanol, ethanol,and isopropanol; ketones such as acetone and methyl ethyl ketone; andpolar solvents such as N,N-dimethylformamide (DMF), dimethyl sulfoxide(DMSO), hexamethylphosphoric triamide, and acetonitrile.

Preferable reducing agents used in chemical reduction are thecombinations of hydrides (e.g., hydrogen iodide, hydrogen sulfide,lithium aluminum hydride, boron hydride, sodium borohydride, and sodiumcyanoborohydride), metals (e.g., tin, zinc, and iron), or metalcompounds (e.g., chromium chloride and chromium acetate) with organic orinorganic acids (e.g., formic acid, acetic acid, propionic acid,trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, andhydrobromic acid).

Preferable catalysts used in catalytic reduction are platinum catalysts(e.g., platinum plates, platinum sponge, platinum black, colloidalplatinum, platinum oxide, and platinum wires), palladium catalysts(e.g., palladium sponge, palladium black, palladium oxide,palladium-carbon, palladium/barium sulfate, and palladium/bariumcarbonate), nickel catalysts (e.g., reduced nickel, nickel oxide, andRaney nickel), cobalt catalysts (e.g., reduced cobalt and Raney cobalt),iron catalysts (e.g., reduced iron), etc.

When these acids used in chemical reduction are in a liquid state, theycan also be used as solvents.

The amount of the reducing agent used in chemical reduction or thecatalyst used in catalytic reduction is not particularly limited and maybe an amount usually used.

The reaction of the present invention can be performed in an atmosphereof inert gas such as nitrogen or argon under the atmospheric pressure orcan be performed under increased pressure.

The reaction temperature is usually 0 to 120° C., preferably roomtemperature to 100° C., more preferably room temperature to 80° C. Thereaction time is usually 30 minutes to 24 hours, preferably 30 minutesto 10 hours, more preferably 30 minutes to 4 hours.

After the completion of the reaction, the reaction product can betreated by a standard method to obtain the compound of the generalformula (2a) of interest.

Reaction Formula-4

wherein R¹, R², R³, X, l, m, and n are defined as above.

The compound represented by the general formula (2b) is produced bysubjecting the compound represented by the general formula (4) and acompound represented by the general formula (7) to cyclization reactionto form a compound represented by the general formula (8) (Step C),which is then reduced (Step D). The reaction conditions are the samereaction conditions as in the Reaction Formula-3.

Reaction Formula-5

wherein R¹, R², R³, R⁴, l, m, n, and X are defined as above; and Y andZ, which are the same or different, each independently represent aleaving group.

Examples of the leaving groups represented by Y and Z in the generalformula (9) include the leaving groups exemplified above.

Step E

The compound represented by the general formula (2) can be produced bysubjecting the compound represented by the general formula (4) and acompound represented by the general formula (9) to cyclization reaction.The cyclization reaction is usually performed in the presence or absenceof a basic compound.

The present reaction is usually performed in a solvent routinely usedthat does not adversely affect the reaction. Examples of the solventinclude: water; alcohol solvents such as methanol, ethanol, isopropanol,n-butanol, trifluoroethanol, and ethylene glycol; ketone solvents suchas acetone and methyl ethyl ketone; ether solvents such astetrahydrofuran, dioxane, diethyl ether, dimethoxyethane, and diglyme;ester solvents such as methyl acetate and ethyl acetate; aprotic polarsolvents such as acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, and N-methylpyrrolidone; halogenated hydrocarbon solventssuch as methylene chloride and ethylene chloride; and other organicsolvents.

A transition metal catalyst and a ligand may be used in this reaction.Examples of the transition metal include ruthenium chloride,dichlorotris(triphenylphosphine)ruthenium,dibromotris(triphenylphosphine)ruthenium,dihydridotetrakis(triphenylphosphine)ruthenium,(η⁴-cyclooctadiene)(η⁶-cyclooctatriene)ruthenium,dichlorotricarbonylruthenium dimers, dodecacarbonyltriruthenium,(η⁵-pentamethylcyclopentadienyl)chloro(η⁴-cyclooctatriene)ruthenium,palladium acetate, palladium chloride,dichlorobis(triphenylphosphine)palladium,tetrakis(triphenylphosphine)palladium,bis(dibenzylideneacetone)palladium, rhodium chloride,chlorotris(triphenylphosphine)rhodium,hydridocarbonyltris(triphenylphosphine)rhodium,hydridotris(triphenylphosphine)rhodium,di-μ-chlorotetracarbonyldirhodium,chlorocarbonylbis(triphenylphosphine)iridium,(η⁵-pentamethylcyclopentadienyl)dichloroiridium dimers, nickeltetrakis(triphenylphosphine), dicobaltoctacarbonyl, and(η⁵-cyclopentadienyl)dicarbonylcobalt.

Examples of the ligand include: unidentate phosphine ligands typified bytrimethylphosphine, triethylphosphine, tri-n-propylphosphine,tri-i-propylphosphine, tri-n-butylphosphine, tri-t-butylphosphine,tricyclohexylphosphine, triphenylphosphine, and tri(o-tolyl)phosphine;bidentate phosphine ligands typified by1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane,1,4-bis(diphenylphosphino)butane, and 1,2-(diethylphosphino)ethane; andphosphite ligands typified by triethyl phosphite, tributyl phosphite,triphenyl phosphite, and tri(o-tolyl) phosphite.

This reaction may be performed in the presence of a base. Inorganic andorganic bases known in the art can be used widely as the base. Examplesof the inorganic bases include alkali metals (e.g., sodium andpotassium), alkali metal bicarbonates (e.g., lithium bicarbonate, sodiumbicarbonate, and potassium bicarbonate), alkali metal hydroxides (e.g.,lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesiumhydroxide), alkali metal carbonates (e.g., lithium carbonate, sodiumcarbonate, potassium carbonate, and cesium carbonate), alkali metallower alkoxides (e.g., sodium methoxide and sodium ethoxide), and alkalimetal hydrides (e.g., sodium hydride and potassium hydride). Examples ofthe organic bases include trialkylamines (e.g., trimethylamine,triethylamine, and N-ethyldiisopropylamine), pyridine, quinoline,piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline,N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN),1,4-diazabicyclo[2.2.2]octane (DABCO), and1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). When these bases are in aliquid state, they can also be used as solvents. These bases are usedalone or as a mixture of two or more of them. The amount of the baseused is usually 0.1 to 10 mol, preferably 0.1 to 3 mol, with respect to1 mol of the compound of the general formula (7).

The reaction can also be performed in the presence of a mixture of anoxidizing agent and a reducing agent.

Examples of the oxidizing agent include manganese dioxide, chromic acid,lead tetraacetate, silver oxide, copper oxide, halogen acid, dimethylsulfoxide (Swern oxidation), organic peroxides, and oxygen. A methodsuch as electrode oxidation may be used.

Examples of the reducing agent include borohydride reagents such assodium borohydride and aluminum hydride reagents such as lithiumaluminum hydride.

The ratio between the compound of the general formula (9) and thecompound of the general formula (4) used in the reaction formula isusually at least 1 mol, preferably approximately 1 to 5 mol of theformer compound with respect to 1 mol of the latter compound.

The reaction of the present invention can be performed in an atmosphereof inert gas such as nitrogen or argon under the atmospheric pressure orcan be performed under increased pressure.

The reaction temperature is not particularly limited. The reaction isusually performed under cooling, at room temperature, or under heating.The reaction is preferably performed under temperature conditionsinvolving room temperature to 100° C., for 30 minutes to 30 hours,preferably 30 minutes to 5 hours.

After the completion of the reaction, the reaction product can betreated by a standard method to obtain the compound of the generalformula (2) of interest.

Examples of preferable salts of the compound of the general formula (1)include pharmacologically acceptable salts, for example: metal saltssuch as alkali metal salts (e.g., sodium salt and potassium salt) andalkaline earth metal salts (e.g., calcium salt and magnesium salt);ammonium salt; salts of inorganic bases such as alkali metal carbonates(e.g., lithium carbonate, potassium carbonate, sodium carbonate, andcesium carbonate), alkali metal bicarbonates (e.g., lithium bicarbonate,sodium bicarbonate, and potassium bicarbonate), and alkali metalhydroxides (e.g., lithium hydroxide, sodium hydroxide, potassiumhydroxide, and cesium hydroxide); salts of organic bases such astri-(lower) alkylamine (e.g., trimethylamine, triethylamine, andN-ethyldiisopropylamine), pyridine, quinoline, piperidine, imidazole,picoline, dimethylaminopyridine, dimethylaniline, N-(lower)alkyl-morpholine (e.g., N-methylmorpholine),1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and 1,4-diazabicyclo [2.2.2] octane (DABCO);inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide,sulfate, nitrate, and phosphate; and organic acid salts such as formate,acetate, propionate, oxalate, malonate, succinate, fumarate, maleate,lactate, malate, citrate, tartrate, carbonate, picrate,methanesulfonate, ethanesulfonate, p-toluenesulfonate, and glutamate.

Moreover, compounds in a form of a solvate (e.g., a hydrate or anethanolate) added to the raw material or the compound of interest shownin each reaction formula are also included in each general formula.Preferable examples of the solvate include hydrates.

Each compound of interest obtained according to each of the reactionformulas can be isolated and purified from the reaction mixture, forexample, by separating, after cooling, the reaction mixture into a crudereaction product by isolation procedures such as filtration,concentration, and extraction and subjecting the crude reaction productto usual purification procedures such as column chromatography andrecrystallization.

The compound represented by the general formula (1) of the presentinvention also encompasses isomers such as geometric isomers,stereoisomers, and optical isomers, of course.

Various isomers can be isolated by a standard method using difference inphysicochemical properties among the isomers. For example, racemiccompounds can be converted to sterically pure isomers by a generaloptical resolution method [e.g., method involving conversion todiastereomeric salts with a general optically active acid (tartaricacid, etc.) and subsequent optical resolution]. Diastereomeric mixturescan be separated by, for example, fractional crystallization orchromatography. Optically active compounds can also be produced usingappropriate optically active starting materials.

The present invention also encompasses isotope-labeled compounds whichare the same as the compound represented by the general formula (1)except that one or more atom(s) is substituted by one or more atoms(s)having a particular atomic mass or mass number. Examples of the isotopethat can be incorporated in the compound of the present inventioninclude hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, andchlorine isotopes such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ¹⁸F, and³⁶Cl. These particular isotope-labeled compounds of the presentinvention containing any of the isotopes and/or other isotopes of otheratoms, for example, radioisotope (e.g., ³H and ¹⁴C)-incorporatedcompounds, are useful in assay for the distribution of drugs and/orsubstrates in tissues. Tritiated (i.e., 3H) and carbon-14 (i.e., ¹⁴C)isotopes are particularly preferable because of their easy preparationand detectability. Furthermore, substitution by heavier isotopes such asheavy hydrogen (i.e., ²H) can be expected to bring about particulartherapeutic advantages attributed to improved metabolic stability, forexample, increased in-vivo half-life, or reduced necessary doses. Theisotope-labeled compounds of the present invention can be preparedgenerally by substituting an unlabeled reagent by an easily obtainableisotope-labeled reagent by a method disclosed in the reaction formulasand/or Examples below.

A pharmaceutical preparation comprising the compound of the presentinvention as an active ingredient will be described.

The pharmaceutical preparation is obtained by making the compound of thepresent invention into usual dosage forms of pharmaceutical preparationsand prepared using a diluent and/or an excipient usually used, such asfillers, extenders, binders, humectants, disintegrants, surfactants, andlubricants.

Such a pharmaceutical preparation can be selected from among variousforms according to a therapeutic purpose. Typical examples thereofinclude tablets, pills, powders, solutions, suspensions, emulsions,granules, capsules, suppositories, and injections (solutions,suspensions, etc.).

Carries known in the art for use for forming a tablet form can be usedwidely. Examples thereof include: excipients such as lactose, sucrose,sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, andcrystalline cellulose; binders such as water, ethanol, propanol, simplesyrup, glucose solutions, starch solutions, gelatin solutions,carboxymethylcellulose, shellac, methylcellulose, potassium phosphate,and polyvinyl pyrrolidone; disintegrants such as dry starch, sodiumalginate, agar powder, laminaran powder, sodium bicarbonate, calciumcarbonate, polyoxyethylene sorbitan fatty acid esters, sodium laurylsulfate, stearic acid monoglyceride, starch, and lactose; disintegrationinhibitors such as sucrose, stearin, cacao butter, and hydrogenated oil;absorption promoters such as quaternary ammonium bases and sodium laurylsulfate; humectants such as glycerin and starch, adsorbents such asstarch, lactose, kaolin, bentonite, and colloidal silicic acid; andlubricants such as purified talc, stearate, boric acid powder, andpolyethylene glycol.

Furthermore, the tablets can be coated, if necessary, with a usualcoating material to prepare, for example, sugar-coated tablets,gelatin-coated tablets, enteric coated tablets, film-coated tablets, andbilayer or multilayer tablets.

Carries known in the art for use for forming a pill form can be usedwidely. Examples thereof include: excipients such as glucose, lactose,starch, cacao butter, hydrogenated plant oil, kaolin, and talc; binderssuch as gum arabic powder, powdered tragacanth, gelatin, and ethanol;and disintegrants such as laminaran and agar.

Carries known in the art for use for forming a suppository form can beused to widely. Examples thereof include polyethylene glycol, cacaobutter, higher alcohol, esters of higher alcohol, gelatin, andsemisynthetic glyceride.

When the compound represented by the general formula (1) is prepared asinjections, solutions, emulsions, and suspensions are preferably sterileand isotonic with blood. Diluents known in the art for use for formingforms of these solutions, emulsions, and suspensions can be used widely.Examples thereof include water, ethanol, propylene glycol, ethoxylatedisostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylenesorbitan fatty acid esters. In this case, the pharmaceutical preparationmay contain common salt, glucose, or glycerin in an amount sufficientfor preparing an isotonic solution and may contain usual solubilizers,buffers, soothing agents, and the like, and if necessary, coloringagents, preservatives, perfumes, flavoring agents, sweetening agents,and the like, and/or other drugs.

The amount of the compound of the present invention contained in thepharmaceutical preparation is not particularly limited and can beselected appropriately from within a wide range. The compound of thepresent invention is usually contained in an amount of preferablyapproximately 1 to 70% by weight in the pharmaceutical preparation.

A method for administering the pharmaceutical preparation according tothe present invention is not particularly limited. The pharmaceuticalpreparation is administered by a method according to various dosageforms, the age, sex, and disease state of a patient, and otherconditions. For example, tablets, pills, solutions, suspensions,emulsions, granules, and capsules are orally administered. Moreover,injections can be administered through an intravenous route alone or asa mixture with a usual replacement fluid such as glucose or amino acidor can be administered alone through intramuscular, intradermal,hypodermic, or intraperitoneal route, if necessary. Suppositories arerectally administered.

The dose of the pharmaceutical preparation may be selected appropriatelyaccording to use, the age, sex, and disease state of a patient, andother conditions. The pharmaceutical preparation is usually administeredonce or several times a day at a daily dose of approximately 0.001 to100 mg, preferably approximately 0.001 to 50 mg, per kg of body weight.

The dose varies depending on various conditions. Thus, in some cases, adose smaller than this range suffices. In other cases, a dose exceedingthis range is required.

A heterocyclic compound of the present invention has reuptake inhibitoryeffects on 1, 2, or 3 monoamines (serotonin, norepinephrine, anddopamine).

The heterocyclic compound of the present invention has remarkably stronguptake inhibitory activity in in-vitro or ex-vivo tests on any one, anytwo, or all of the 3 monoamines, compared with existing compounds havingmonoamine uptake inhibitory activity. Moreover, the heterocycliccompound of the present invention exhibits remarkably strong activity inbrain microdialysis study against increase in any one, any two, or allof the 3 monoamines, compared with existing compounds having monoamineuptake inhibitory activity.

The heterocyclic compound of the present invention has a widetherapeutic spectrum, compared with antidepressants known in the art.

The heterocyclic compound of the present invention exerts sufficienttherapeutic effects even in short-term administration.

The heterocyclic compound of the present invention has excellentbioavailability, weak inhibitory activity on metabolic enzymes in theliver, few side effects, and excellent safety.

The heterocyclic compound of the present invention is excellent intransfer into the brain.

The heterocyclic compound of the present invention also exerts strongactivity in a mouse forced swimming test used in depression screening.Moreover, the heterocyclic compound of the present invention also exertsstrong activity in a rat forced swimming test used in depressionscreening. Moreover, the heterocyclic compound of the present inventionalso exerts strong activity in a reserpine-induced hypothermia test usedin depression screening.

The heterocyclic compound of the present invention exerts strongactivity in a marble burying behavior test of anxiety or stress diseasemodel mice and in fear-conditioned stress models.

The heterocyclic compound of the present invention has reuptakeinhibitory effects on 1, 2, or 3 monoamines (serotonin, norepinephrine,and dopamine) and is therefore effective for treating various disordersassociated with the reduced neurotransmission of serotonin,norepinephrine, or dopamine.

Such disorders include depression (e.g.: major depressive disorder;bipolar I disorder; bipolar II disorder; mixed state; dysthymicdisorder; rapid cycler; atypical depression; seasonal affectivedisorder; postpartum depression; hypomelancholia; recurrent briefdepressive disorder; refractory depression/chronic depression; doubledepression; alcohol-induced mood disorder; mixed anxiety-depressivedisorder; depression caused by various physical diseases such as Cushingsyndrome, hypothyroidism, hyperparathyroidism, Addison's disease,amenorrhea-galactorrhea syndrome, Parkinson's disease, Alzheimer'sdisease, cerebrovascular dementia, brain infarct, brain hemorrhage,subarachnoid hemorrhage, diabetes mellitus, virus infection, multiplesclerosis, chronic fatigue syndrome, coronary artery disease, pain, andcancer, etc.; presenile depression, senile depression; depression inchildren and adolescents; depression induced by drugs such asinterferon, etc.), depression status caused by adjustment disorder,anxiety caused by adjustment disorder, anxiety caused by variousdiseases [e.g.: nerve disorders (head injury, brain infection, and innerear impairment); cardiovascular disorders (cardiac failure andarrhythmia); endocrine disorders (hyperadrenalism and hyperthyroidism);and respiratory disorders (asthma and chronic obstructive pulmonarydisease)], generalized anxiety disorder, phobia (e.g., agoraphobia,social fear, simple phobia, social phobia, social anxiety disorder,ereuthrophobia, anthrophobia, acrophobia, odontophobia, trypanophobia,specific phobia, simple phobia, animal phobia, claustrophobia,nyctophobia and phobic anxiety), obsessive-compulsive disorder, panicdisorder, posttraumatic stress disorder, acute stress syndrome,hypochondriasis disorder, dissociative amnesia, avoidant personalitydisorder, body dysmorphic disorder, eating disorders (e.g., anorexianervosa and bulimia nervosa), obesity, chemical dependence (e.g.,addition to alcohol, cocaine, heroin, phenobarbital, nicotine, andbenzodiazepines), pain (e.g., chronic pain, psychogenic pain,neuropathic pain, phantom limb pain, postherpetic neuralgia, traumaticcervical syndrome, spinal cord injury (SCI) pain, trigeminal neuralgia,diabetic neuropathy), fibromyalgia (FMS), Alzheimer's disease, memorydeficit (e.g., dementia, amnestic disorder, and age-related cognitivedecline (ARCD)), Parkinson's disease (e.g., non-motor/psychoticsymptoms, dementia in Parkinson disease, neuroleptic-induced Parkinson'ssyndrome, and tardive dyskinesia), restless leg diseases, endocrinedisorders (e.g., hyperprolactinemia), vasospasm (particularly, in thecerebral vasculature), cerebellar ataxia, gastrointestinal disorders(which encompass changes in secretion and motility), negative syndromesof schizophrenia, premenstrual syndrome, stress urinary incontinence,Tourette's Disorder, attention deficit hyperactivity disorder (ADHD),autism, Asperger syndrome, impulse control disorder, trichotillomania,kleptomania, gambling disorder, cluster headache, migraine, chronicparoxysmal hemicrania, chronic fatigue syndrome, precocious ejaculation,male impotence, narcolepsy, primary hypersomnia, cataplexy, sleep apneasyndrome and headache (associated with angiopathy).

EXAMPLES

Hereinafter, the present invention will be described more specificallywith reference to Reference Examples, Examples, and PharmacologicalTests. The chemical structures of racemic bodies and optically activeforms are indicated, for example, as shown below.

Racemic Body

Relative Configuration

Optically Active FormAbsolute Configuration

Reference Example 1 Production ofcis-3,3-dimethyloctahydrocyclopentapyrazin-2-one

Relative Configuration

90% acetone cyanohydrin (9.79 g, 104 mmol) was added to an aqueous (100mL) solution of cis-cyclopentane-1,2-diamine (9.88 g, 98.6 mmol) at roomtemperature, and the mixture was stirred under reflux for 16 hours. Thesolvent was removed from the reaction mixture under reduced pressure,followed by azeotropy with ethanol. The obtained residue was purified bysilica gel column chromatography (methylene chloride/methanol=1/10) toobtain cis-3,3-dimethyloctahydrocyclopentapyrazin-2-one (5.00 g, 30%) ina white powder form.

¹H-NMR(CDCl₃)δppm: 1.20(1 H,brs),1.34(3 H,s),1.39(3 H,s),1.40-2.20(6H,m),3.50-3.70(2 H,m),5.89(1 H,brs).

Compounds of Reference Examples 2 to 12 shown below were produced in thesame way as in Reference Example 1 using appropriate starting materials.

Reference Example 2

Trans-3,3-dimethyloctahydrocyclopentapyrazin-2-one

Relative Configuration

¹H-NMR(CDCl₃)δppm: 1.26-1.55(9 H,m),1.75-2.00(4 H,m),2.85-3.02(1H,m),3.05-3.20(1 H,m),6.02(1 H,brs).

Reference Example 3 Cis-3,3-dimethylhexahydrofuro[3,4-b]pyrazin-2-one

Relative Configuration

¹H-NMR(CDCl₃)δppm: 1.37(3H,s), 1.40(3H,s),1.50-1.85(1H,br),3.73-4.10(6H,r),6.02-6.22(1H,br).

Reference Example 4 Trans-3,3-dimnethylhexahydrofuro[3,4-b]pyrazin-2-one

Relative Configuration

¹H-NMR(CDCl₃)δppm: 1.38-1.43 (1H, br), 1.44 (3H, s), 1.47 (3H, s),3.38-3.52 (1H, m), 3.52-3.65 (3H, m), 4.00-4.14 (2H, m), 6.28-6.45 (1H,br).

Reference Example 5 (4aS,8aS)-3,3-dimethyloctahydroquinoxalin-2-one

Absolute Configuration

¹H-NMR(CDCl₃)δppm: 1.14-1.37 (6H, m), 1.38 (3H, s), 1.42 (3H, s) 1.69(1H, brs), 1.74-1.84 (2H, m), 2.57-2.65 (1H, m), 2.96-3.04 (1H, m),5.61(1H,s)

Reference Example 6 (4aR,8aR)-3,3-dimethyloctahydroquinoxalin-2-one

Absolute Configuration

¹H-NMR(CDCl₃)δppm: 1.14-1.37 (6H, m), 1.38 (3H, s), 1.42 (3H, s), 1.63(1H, brs), 1.73-1.83 (2H, m), 2.57-2.66 (1H, m), 2.95-3.04 (1H, m), 5.55(1H, s)

Reference Example 7 Trans-3,3-diethyloctahydroquinoxalin-2-one

Relative Configuration

¹H-NMR(CDCl₃)δppm: 0.92 (3H, t, J=7.5 Hz), 0.93 (3H,t, J=7.3 Hz),1.13-1.49 (7H, m), 1.60-1.99 (6H, m), 2.55-2.60 (1H, m), 2.91-3.00 (1H,m), 5.69(1H, brs)

Reference Example 8Trans-octahydro-1′H-spiro[cyclobutane-1,2′-quinoxalin]-3′-one

Relative Configuration

¹H-NMR(CDCl₃)δppm: 1.14-1.46 (4H, m), 1.70-2.17 (9H, m), 2.43-2.52 (1H,m), 2.55-2.66 (1H, m), 2.78-2.88 (1H, m), 2.97-3.06 (1H, m), 5.65 (1H,brs)

Reference Example 9Cis-octahydro-1′H-spiro[cyclobutane-1,2′-quinoxalin]-3′-one

Relative Configuration

¹H-NMR(CDCl₃)δppm: 1.1-1.3 (1H, m), 1.35-2.1 (12H, m), 2.5-2.6 (1H, m),2.75-2.85 (1H, m), 3.15-3.3 (2H, m), 5.65(1H, br).

Reference Example 10 6Trans-octahydro-1′H-spiro[cyclohexane-1,2′-quinoxalin]-3′-one

Relative Configuration

1H-NMR(CDCl₃)δppm: 1.18-1.88 (18H, m), 2.03-2.13 (1H, m), 2.47-2.58 (1H,m), 2.92-3.00 (1H, m), 5.59 (1H, s)

Reference Example 11 Cis-3,3-dimethyldecahydrocyclobeptapyrazin-2-one

Relative Configuration

¹H-NMR(CDCl₃)δppm: 1.12-2.00 (16 H, m), 2.03-2.20 (1H, m), 3.35-3.55(2H, m), 5.88 (1H, brs).

Reference Example 12 Trans-3,3-dimethyldecahydrocycloheptapyrazin-2-one

Relative Configuration

¹H-NMR(CDCl₃)δppm: 1.35 (3H, s), 1.39 (3H, s), 1.42-1.90 (11H, m),2.73-2.85 (1H, m), 3.13-3.26 (1H, m), 5.51 (1H, brs).

Reference Example 13 Production ofcis-4,4-dimethyloctahydrocyclopenta[b][1,4]diazepin-2-one

Relative Configuration

A toluene (200 mL) suspension of cis-cyclopentane-1,2-diamine (19.7 g,197 mmol) and 3-methyl-2-butenoic acid (19.7 g, 197 mmol) was stirredunder reflux for 24 hours under azeotropic conditions using a Dean-Starkapparatus. The reaction mixture was cooled to room temperature and thenconcentrated under reduced pressure, and the deposited crystal wascollected by filtration. The obtained crystal was washed with ether andthen dried to obtaincis-4,4-dimethyloctahydrocyclopenta[b][1,4]diazepin-2-one (8.60 g, 24%)in a light brown powder form.

¹H-NMR(CDCl₃)δppm: 1.10-1.56 (10 H, m), 1.65-1.80 (1 H, m), 2.02-2.30 (3H, m), 2.60(1 H, d,J=12.8 Hz), 3.18-3.37 (1 H, m), 3.68-3.85 (1 H, m),5.73(1H,brs).

Compounds of Reference Examples 14 and 15 below were produced in thesame way as in Reference Example 13 using appropriate startingmaterials.

Reference Example 14(5aS,9aS)-4,4-dimethyldecahydro[b][1,4]diazepin-2-one

Absolute Configuration

¹H-NMR(CDCl₃)δppm: 1.00-1.45 (11H, m), 1.63-1.83 (3H, mm), 1.83-2.00(1H, m), 2.31-2.43 (1H, m), 2.65-2.81 (2H, m), 3.00-3.16 (1H, m),5.54-5.90 (1H, br).

Reference Example 15(5aR,9aR)-4,4-dimethyldecahydro[b][1,4]diazepin-2-one

¹H-NMR(CDCl₃)δppm: 1.02-1.36 (11H, m), 1.64-1.83 (3H, m), 1.83-1.97 (1H,m), 2.37 (1H, dd, J=2.4, 13.9 Hz), 2.66-2.81 (2H, m), 3.01-3.15 (1H, m),5.75-5.92 (1H, brs).

Reference Example 16 Production ofcis-2,2-dimethyloctahydro-1H-cyclopenta[b]pyrazine

Relative Configuration

Lithium aluminum hydride (541 mg, 14.3 mmol) was added to an anhydrousdioxane (40 mL) solution ofcis-3,3-dimethyloctahydrocyclopentapyrazin-2-one (2.00 g, 11.9 mmol)with stirring at room temperature, and the mixture was gradually heatedand stirred for 10 minutes under reflux. The reaction mixture was cooledto ice temperature. Then, sodium sulfate decahydrate was added theretoin small portions until no hydrogen gas was generated. Then, the mixturewas stirred at room temperature for 1 hour. Insoluble matter wasfiltered through celite, and the filtrate was concentrated. The obtainedresidue was purified by basic silica gel column chromatography (ethylacetate/hexane=1/10) to obtaincis-2,2-dimethyloctahydro-1H-cyclopenta[b]pyrazine (1.67 g, 91%) in apale yellow oil form.

¹H-NMR(CDCl₃)δppm: 1.04 (3 H, s), 1.16 (3 H, s), 1.28-2.02 (8 H, m),2.37 (1 H, d, J=12.9 Hz), 2.70 (1 H, d, J=12.9 Hz), 3.00-3.15 (1 H, m),3.15-3.32 (1 H, m).

Compounds of Reference Examples 17 to 34 below were produced in the sameway as in Reference Example 16 using appropriate starting materials.

Reference Example 17Trans-2,2-dimethyloctahydro-1H-cyclopenta[b]pyrazine

Relative Configuration

¹H-NMR(CDCl₃)δppm: 1.08 (3H, s), 1.19-1.92 (11H, m), 2.15-2.30 (1H, m),2.55-2.74 (2H, m), 2.77 (1H, d, J=12.2 Hz).

Reference Example 18Cis-2,2-dimethyldecahydrocyclopenta[b][1,4]diazepine

Relative Configuration

¹H-NMR(CDCl₃)δppm: 1.11 (3H, s), 1.14 (3H, s), 1.15-1.45 (6H, m),1.55-1.67 (1H, m), 1.67-1.77 (1H, m), 1.97-2.12 (2H, m), 2.68-2.80 (1H,m), 2.98-3.11 (2H, m), 3.16-3.28 (1H, m).

Reference Example 19 Cis-2,2-dimethyloctahydrofuro[3,4-b]pyrazine

Relative Configuration

¹H-NMR(CDCl₃)δppm: 1.08 (3H, s), 1.18 (3H, s), 1.40-1.80 (2H, br),2.41(1 H, d, J=13.2 Hz), 2.69 (1H, d, J=13.2 Hz), 3.33-3.43 (1H, m),3.43-3.55 (1H, m), 3.63-3.72 (1 H,m), 3.75-3.96 (3H, m).

Reference Example 20 Trans-2,2-dimethyloctahydrofuro[3,4-b]pyrazine

Relative Configuration

¹H-NMR(CDCl₃)δppm: 1.13 (3H, s), 1.30 (3H, s), 1.44-1.65 (2H, m),2.64-2.78 (2H, m), 2.83 (1H, d, J=12.2 Hz), 3.11-3.22 (1H, m), 3.46 (1H,dd, J=7.3, 10.5 Hz), 3.55 (1H, dd, J=7.4, 10.5 Hz), 3.94 (1H, t, J=7.1Hz), 4.00 (1H, t, J=7.2 Hz).

Reference Example 21 Cis-2,2-dimethyldecahydro-1H-benzo[b][1,4]diazepine

Relative Configuration

¹H-NMR(CDCl₃)δppm: 1.08 (3H, s), 1.13 (3H, s), 1.18-1.84 (12H, m),2.65-2.93 (3H, m), 3.14-3.22 (1H, m).

Reference Example 22(5aS,9aS)-2,2-dimethyldecahydro-1H-benzo[b][1,4]diazepine

Absolute Configuration

¹H-NMR(CDCl₃)δppm: 1.00-1.35 (11H, m), 1.50-1.85 (7H, m), 2.20-2.31 (1H,m), 2.31-2.43 (1H,m), 2.79-2.90 (1H, m), 2.90-3.04 (1H, m).

Reference Example 23(5aR,9aR)-2,2-dimethyldecahydro-1H-benzo[b][1,4]diazepine

Absolute Configuration

¹H-NMR(CDCl₃)δppm: 1.00-1.35 (11H, m), 1.50-1.85 (7H, m), 2.20-2.31 (1H,m), 2.31-2.43 (1H, m), 2.79-2.90 (1H, m), 2.90-3.04 (1H, m).

Reference Example 24 Cis-2,2-dimethyldecahydroquinoxaline

Relative Configuration

¹H-NMR(CDCl₃)δppm: 1.06 (3H, s), 1.19 (3H, s), 1.20-1.40 (5H, m),1.53-1.60 (3H, m), 1.70-1.77 (1H, m), 1.92-2.15 (1H, m), 2.36 (1H, d,J=12.7 Hz), 2.66-2.72 (1H, m), 2.72 (1H, d, J=12.7 Hz), 3.16-3.28 (1H,m).

Reference Example 25 Trans-2,2-dimethyldecahydroquinoxaline

Relative Configuration

¹H-NMR(CDCl₃)δppm: 1.05 (3H, s), 1.08-1.74 (10H, m), 1.23 (3H, s),2.02-2.12 (1H, m), 2.40-2.50 (1H, m), 2.60 (1H, d, J=12.1 Hz), 2.73 (1H,d, J=12.1 Hz).

Reference Example 26 (4aS,8aS)-2,2-dimethyldecahydroquinoxaline

Absolute Configuration

¹H-NMR(CDCl₃)δppm: 1.01-1.43 (6H, m), 1.05 (3H, s), 1.23 (3H, s),1.58-1.63 (1H, m), 1.68-1.74 (3H, m), 2.03-2.19 (1H, m), 2.40-2.49 (1H,m), 2.60 (1H, d, J=12.1 Hz), 2.73 (1H, d, J=12.1 Hz).

Reference Example 27 (4aR,8aR)-2,2-dimethyldecahydroquinoxaline

Absolute Configuration

¹H-NMR(CDCl₃)δppm: 1.05 (3H, s), 1.09-1.56 (6H, m), 1.23 (3H, s),1.58-1.63 (1H, m), 1.66-1.75 (3H, m), 2.03-2.12 (1H, m), 2.41-2.50 (1H,m), 2.61 (1H, d, J=12.1 Hz), 2.75 (1H, d, J=12.1 Hz).

Reference Example 28 Trans-2,2-diethyldecahydroquinoxaline

Relative Configuration

¹H-NMR(CDCl₃)δppm: 0.79 (3H, t, J=7.5 Hz), 0.81 (3H, t, J=7.5 Hz),0.86-1.02 (1H, m), 1.08-1.40 (8H, m), 1.47-1.60 (2H, m), 1.67-1.87 (3H,m), 2.06-2.15 (1H, m), 2.33-2.42 (1H, m), 2.57 (1H, d, J=12.1 Hz), 2.81(1H, d, J=12.1 Hz).

Reference Example 29Trans-octahydro-1′H-spiro[cyclobutane-1,2′-quinoxaline]

Relative Configuration

Reference Example 30Cis-octahydro-1′H-spiro[cyclobutane-1,2′-quinoxaline]

Relative Configuration

Reference Example 31Trans-octahydro-1′H-spiro[cyclopentane-1,2′-quinoxaline]

Relative Configuration

¹H-NMR(CDCl₃)δppm: 1.10-1.97 (18H, m), 2.10-2.21 (1H, m), 2.29-2.38 (1H,m), 2.71 (1H, d, J=12.2 Hz), 2.76 (1H, d, J=12.2 Hz).

Reference Example 32Trans-octahydro-1′H-spiro[cyclohexane-1,2′-quinoxaline]

Relative Configuration

¹H-NMR(CDCl₃)δppm: 1.12-1.76 (20H, m), 2.12-2.20 (1H, m), 2.44-2.53 (1H,m), 2.55 (1H, d, J=12.2 Hz), 2.98 (1H, d, J=12.2 Hz).

Reference Example 33 Cis-2,2-dimethyldecahydro-1H-cyclohepta[b]pyrazine

Relative Configuration

¹H-NMR(CDCl₃)δppm: 1.00-2.02 (18H, m), 2.42 (1H, d, J=12.4 Hz), 2.58(1H, d, J=12.4 Hz), 2.75-2.86 (1H, m), 3.13-3.25 (1H, m).

Reference Example 34Trans-2,2-dimethyldecahydro-1H-cyclohepta[b]pyrazine

Relative Configuration

¹H-NMR(CDCl₃)δppm: 1.05 (3H,s), 1.21 (3H, s), 1.23-1.80 (12H, m),2.09-2.20 (1H, m), 2.46-2.60 (2H, m), 2.68 (1H, d, J=11.8 Hz).

Reference Example 35 Production of(2RS,4aSR,8aSR)-2-ethyldecahydroquinoxaline

Relative Configuration

Dichloro(pentamethylcyclopentadienyl)iridium (III) dimer (70 mg, 0.090mmol) and sodium bicarbonate (73 mg, 0.87 mmol) were added to an aqueous(20 mL) solution of trans-cyclohexane-1,2-diamine (2.00 g, 17.5 mmol)and (±)-1,2-butanediol (1.69 mL, 18.4 mmol) with stirring at roomtemperature. Degassing and argon substitution were repeated 3 times, andthe mixture was then stirred for 24 hours under reflux. The reactionmixture was concentrated under reduced pressure. The obtained residuewas purified by basic silica gel column chromatography (methylenechloride/methanol) to obtain (2R*,4aS*,8aS*)-2-ethyldecahydroquinoxaline(2.03 g, yield: 69%) in a yellow solid form.

¹H-NMR(CDCl₃)δppm: 0.92 (3H, t, J=7.5 Hz), 1.10-1.60 (7H, m), 1.64-1.83(5H, m), 2.16-2.31 (2H, m), 2.44 (1H, dd, J=11.5, 10.4 Hz), 2.58-2.67(1H, m), 3.02 (1H, dd, J=11.5, 2.7 Hz).

Reference Example 36 Production of(4aS,8aS)-1-benzyldecahydroquinoxaline

Absolute Configuration

Benzaldehyde (3.05 mL, 30.0 mmol) was added to a methanol (300 mL)solution of (1S,2S)-cyclohexane-1,2-diamine (3.43 g, 30.0 mmol) withstirring at room temperature, and the mixture was stirred overnight atthe same temperature. The reaction mixture was cooled to 0° C. Sodiumborohydride (2.27 g, 60.0 mmol) was added thereto, and the mixture wasstirred at 0° C. for 2 hours. To the reaction mixture, water (30 mL) wasadded, and the product was extracted twice with methylene chloride (50mL). The organic layers were combined and dried over magnesium sulfate,and the solvent was then distilled off under reduced pressure. Theobtained residue was purified by basic silica gel column chromatography(ethyl acetate/hexane) to obtain (1S,2S)-N-benzylcyclohexane-1,2-diamine(cas no. 207450-11-1) (2.95 g, yield: 48%) in a pale yellow oil form.

The obtained (1S,2S)-N-benzylcyclohexane-1,2-diamine (2.90 g, 14.2 mmol)was dissolved in methylene chloride (284 nL). To the solution, 60%sodium hydride (1.99 g, 49.7 mmol) was added with ice-cooling andstirring in a nitrogen atmosphere. After 5 minutes, (2-1.5bromoethyl)diphenylsulfonium trifluoromethanesulfonate (6.92 g, 15.6mmol) was added to the reaction mixture with ice-cooling and stirring,and the mixture was stirred overnight at room temperature. To thereaction mixture, a saturated aqueous solution of ammonium chloride wasadded dropwise in small portions, and the product was then extractedtwice with methylene chloride (100 mL). The organic layers were combinedand dried over magnesium sulfate, and the solvent was then distilled offunder reduced pressure. The obtained residue was purified by NH-silicagel column chromatography (ethyl acetate/hexane) to obtain(4aS,8aS)-1-benzyldecahydroquinoxaline (2.28 g, 70%) in a light brownsolid form.

¹H-NMR(CDCl₃)δppm: 1.05-1.4 (4H, m), 1.50 (1H, br), 1.6-1.9 (4H, m),2.05-2.2 (1H, m), 2.2-2.3 (1H, m), 2.4-2.5 (1H, m), 2.65-2.75 (1H, m),2.8-2.95 (2H, m), 3.14 (1H, d, J=13.4 Hz), 4.11 (1H, d, J=13.4 Hz),7.15-7.4 (5H, m).

Compounds of Reference Examples 37 to 39 below were produced in the sameway as in Reference Example 36 using appropriate starting materials.

Reference Example 37 (4aS,8aS)-1-benzyldecahydroquinoxaline

Absolute Configuration

¹H-NMR(CDCl₃)δppm: 1.05-1.4 (4H, m) 1.50 (1H, br), 1.6-1.9 (4H, m)2.05-2.2 (1H, m), 2.2-2.3 (1H, m), 2.4-2.5 (1H, m), 2.65-2.75 (1H, m),2.8-2.95 (2H, m), 3.13 (1H, d, J=13.4 Hz), 4.11 (1H, d, J=13.4 Hz),7.15-7.4 (5H, m).

Reference Example 38 Cis-decahydroquinoxaline-1-carboxylic acidtert-butyl ester

Relative Configuration

¹H-NMR(CDCl₃)δppm: 1.05-1.15 (1H, m), 1.2-1.75(19H, m), 1.75-1.85 (1H,m), 1.85-2.2 (1H, m), 3.70 (1H, br),4.83(1H, br).

Reference Example 39 Cis-1-benzyldecahydroquinoxaline

Relative Configuration

¹H-NMR(CDCl₃)δppm: 1.0-2.0 (10H, m), 2.2-2.4 (1H, m), 2.45-2.7 (2H, m),2.75-3.1 (2H, m), 3.63 (2H, br), 7.05-7.45 (5H, m).

Reference Example 40 Production of(4aR,8aS)-2,2-dimethyldecahydecahydroquinoxalineu

Absolute Configuration

Reference Example 41 (4aS,8aR)-2,2-dimethyidecahydroquinoxaline

Absolute Configuration

(−)-dibenzoyl-L-tartaric acid monohydrate (13.8 g, 36.7 mmol) in ethanol(140 mL) was added to an ethanol (140 mL) solution ofcis-2,2-dimethyldecahydroquinoxaline (13.7 g, 81.4 mmol) with stirringat room temperature. The reaction mixture was stirred for 30 minutesunder reflux and cooled to room temperature, and the deposited whitecrystal was then collected by filtration. The obtained crystal waswashed with ethanol (20 mL) and then dried to obtain a white solid <1>(13.1 g). The filtrate and washes obtained in obtaining the solid <1>were concentrated under reduced pressure. The obtained residue wasdissolved in ethanol (100 mL). To the solution, an ethanol (130 mL)solution of (+)-dibenzoyl-D-tartaric acid (13.1 g, 36.6 mmol) was addedwith stirring at room temperature, and the deposited crystal wascollected by filtration. The obtained crystal was washed with ethanol(20 mL) and then dried to obtain a light brown solid <2> (16.6 g).

A methanol (130 mL)/water (10 mL) suspension of the solid <1> wasstirred for 30 minutes under reflux. Then, the reaction mixture wascooled to room temperature, and the deposited crystal was collected byfiltration. The deposited crystal was washed with methanol (10 mL) andthen dried to obtain (4aR,8aS)-2,2-dimethyldecahydroquinoxalinedibenzoyl-L-tartrate (11.4 g, 21.6 mmol) in a white solid form (theabsolute configuration of cis-2.2-dimethyldecahydroquinoxaline wasdetermined by the X-ray crystallographic analysis of the white solid).This solid was dissolved in a 1 N aqueous sodium hydroxide solution (44mL), and the product was extracted with ether (100 mL) three times andwith methylene chloride (100 mL) three times. The extracted organiclayers were combined, dried over magnesium sulfate, and thenconcentrated under reduced pressure to obtain(4aR,8aS)-2,2-dimethyldecahydroquinoxaline (3.44 g, yield: 25%) in awhite solid form.

¹H-NMR(CDCl₃)δppm: 1.06 (3H, s), 1.20 (3H, s), 1.2-1.4 (4H, m),1.45-1.95 (5H, m), 1.95-2.15 (1H, m), 2.36 (1H, d, J=12.7 Hz), 2.65-2.75(2H, m), 3.15-3.25 (1H, m).

A methanol (130 mL)/water (10 mL) suspension of the solid <2> wasstirred for 1 hour under reflux. Then, the reaction mixture was cooledto room temperature, and the deposited crystal was collected byfiltration. The deposited crystal was washed with methanol (10 mL) andthen dried to obtain (4aS,8aR)-2,2-dimethyldecahydroquinoxalinedibenzoyl-D-tartrate (16.0 g, 30.4 mmol) in a white solid form. Thissolid was dissolved in a 1 N aqueous sodium hydroxide solution (65 mL),and the product was extracted with methylene chloride (100 mL) threetimes. The extracted organic layers were combined, dried over magnesiumsulfate, and then concentrated under reduced pressure to obtain(4aS,8aR)-2,2-dimethyldecahydroquinoxaline (4.63 g, yield: 34%) in alight brown solid form.

¹H-NMR(CDCl₃)δppm: 1.06 (3H, s), 1.19 (3H, s), 1.2-1.45 (5H, m),1.45-1.65 (3H, m), 1.65-1.8 (1H, m), 1.95-2.15 (1H, m), 2.36 (1H, d,J=12.7 Hz), 2.6-2.8 (2H, m), 3.15-3.25 (1H, m).

Compounds of Reference Examples 42 to 45 below were produced in the sameway as in Reference Examples 40 and 41 using appropriate startingmaterials.

Reference Example 42(4a′R,8a′S)-octahydro-1′H-spiro[cyclobutane-1,2′-quinoxaline]

Absolute Configuration

¹H-NMR (CDCl₃) δppm: 1.20-2.20 (16H, m), 2.69 (1H, d, J=12.4 Hz),2.72-2.82 (1H, m), 2.87-3.02 (2H, m).

Reference Example 43(4a′S,8a′R)-octahydro-1′H-spiro[cyclobutane-1,2′-quinoxaline]

Absolute Configuration

¹H-NMR (CDCl₃) δppm: 1.20-2.20 (16H, m), 2.68 (1H, d, J=12.5 Hz),2.72-2.82 (1H, m), 2.87-3.02 (2H, m).

Reference Example 44 (4aR,8aS)-1-benzyldecahydroquinoxaline

Absolute Configuration

¹H-NMR(CDCl₃)δppm: 1.0-1.25 (1H, m), 1.25-1.65 (5H, m), 1.65-2.05 (3H,m), 2.2-2.4 (1H, m), 2.45-2.7 (2H, m), 2.75-3.1 (3H, m), 3.63 (2H, br),7.15-7.4 (5H, m).

Reference Example 45 (4aS,8aR)-1-benzyldecahydroquinoxaline

Absolute Configuration

¹H-NMR(CDCl₃)δppm: 1.05-1.25 (1H, m), 1.25-1.65 (5H, m), 1.65-2.05 (3H,m), 2.2-2.4 (1H, m), 2.5-2.7 (2H, m), 2.75-3.1 (3H, m), 3.63 (2H, br),7.15-7.4 (5H, m).

Reference Example 46 Production of(trans-3-oxodecahydroquinoxalin-1-yl)acetic acid ethyl ester

Relative Configuration

Trans-cyclohexane-1,2-diamine (3.00 g, 26.3 mmol) was diluted withethanol (15 ml). To the solution, bromoethyl acetate (6.12 mL, 55.2mmol) was added dropwise with ice-cooling, and the mixture was thenstirred overnight at room temperature.

To the reaction solution, water was added, and the mixture was stirred.The product was extracted with methylene chloride. The organic layer waswashed with saturated saline and dried over magnesium sulfate, followedby filtration. The filtrate was concentrated under reduced pressure. Theobtained residue was separated and purified by silica gel columnchromatography (methylene chloride/methanol) to obtain(trans-3-oxodecahydroquinoxalin-1-yl)acetic acid ethyl ester (2.35 g,yield: 74.4%) in an orange particulate solid form.

¹H-NMR(CDCl₃)δppm: 1.13-1.41 (4H, m), 1.28 (3H, t, J=7.1 Hz), 1.72-1.97(4H, m), 2.59-2.67 (1H, m), 3.06-3.13 (1H, m), 3.35 (1H, d, J=17.4 Hz),3.48 (1H, d, J=16.8 Hz), 3.52 (1H, d, J=17.4 Hz), 3.60 (1H, d, J=16.8Hz), 4.17 (2H, q, J=7.1 Hz), 6.79 (1H, brs).

Reference Example 47 Production of2-(trans-decahydroquinoxalin-1-yl)ethanol

Relative Configuration

Lithium aluminum hydride (1.00 g, 26.4 mmol) was suspended in anhydrousdioxane (40 ml). To the suspension, an anhydrous dioxane (10 ml)solution of (trans-3-oxodecahydroquinoxalin-1-yl)acetic acid ethyl ester(2.35 g, 9.78 mmol) was added dropwise with stirring at roomtemperature, and the mixture was then stirred under reflux for 10minutes. The reaction mixture was cooled on ice, and sodium sulfatedecahydrate was added thereto in small portions until no gas wasgenerated. This mixture was filtered through celite and washed withmethylene chloride, and the filtrate was then concentrated under reducedpressure to obtain 2-(trans-decahydroquinoxalin-1-yl)ethanol (1.74 g,yield: 97%) in a brown oil form.

¹H-NMR(CDCl₃)δppm: 0.95-1.1 (1H, m), 1.15-1.44 (3H, m), 1.68-1.80(5H,m), 1.85-1.94 (1H, m), 2.05-2.44 (4H, m), 2.87-2.97 (3H, m),3.04-3.16 (1H, m), 3.46-3.54 (1H, m), 3.60-3.69 (1H, m).

Reference Example 48 Production oftrans-1-[2-(tert-butyldimethylsilyloxy)ethyl]decahydroquinoxaline

Relative Configuration

Triethylamine (4.61 mL, 33.0 mmol) and subsequentlytert-butyldimethylsilyl chloride (4.27 g, 28.3 mmol) were added to amethylene chloride (40 mL) solution of2-(trans-decahydroquinoxalin-1-yl)ethanol (1.74 g, 9.44 mmol) withice-cooling and stirring, and the mixture was stirred overnight at roomtemperature. To the reaction mixture, water (100 mL) was added toterminate the reaction. The product was extracted with methylenechloride (100 mL). The organic layer was washed with water twice andwith saturated saline once, then dried over magnesium sulfate, andconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (methylene chloride/methanol) toobtain trans-1-[2-(tert-butyldimethylsilyloxy)ethyl]decahydroquinoxaline(2.00 g, yield: 71%) in a light brown oil form.

¹H-NMR(CDCl₃)δppm: 0.06 (6H, s), 0.89 (9H, s), 0.98-1.36 (4H, m),1.65-1.79 (4H, m), 1.85-1.95 (1H, m), 2.08-2.14 (1H, m), 2.24-2.39 (1H,m), 2.45-2.61 (2H, m), 2.79-3.03 (4H, m), 3.62-3.80 (2H, m).

Compounds of Reference Examples 50 and 51 below were produced in thesame way as in Reference Example 1 using appropriate starting materials.

Reference Example 50(4a′S,8a′S)-octahydro-1′H-spiro[cyclobutane-1,2′-quinoxalin]-3′-one

Absolute Configuration

¹H-NMR(CDCl₃)δppm: 0.99-1.38 (4H, m), 1.55-1.78 (5H, m), 1.78-1.94 (3H,m), 2.21-2.33 (2H, m), 2.48-2.59 (1H, m), 2.63 (1H, brs), 2.76-2.87 (1H,m), 7.36 (1H, s).

Reference Example 51

(4a′R,8a′R)-octahydro-1′H-spiro[cyclobutane-1,2′-quinoxalin]-3′-one

Absolute Configuration

¹H-NMR(CDCl₃)δppm: 0.97-1.36 (4H, m), 1.55-1.77 (5H, m), 1.77-1.92 (3H,m), 2.20-2.32 (2H, m), 2.47-2.57 (1H, m), 2.63 (1H, brs), 2.76-2.86 (1H,m), 7.36 (1H, s).

Compounds of Reference Examples 52 and 53 below were produced in thesame way as in Reference Example 16 using appropriate startingmaterials.

Reference Example 52(4a′S,8a′S)-octahydro-1′H-spiro[cyclobutane-1,2′-quinoxaline]

Absolute Configuration

¹H-NMR (CDCl₃) δppm: 1.05-1.90 (15H, m), 2.15-2.30 (3H, m), 2.69 (1 H,dd, J=1.5, 12.2 Hz), 3.01 (1H, d, J=12.2 Hz).

Reference Example 53(4a′R,8a′R)-octahydro-1′H-spiro[cyclobutane-1,2′-quinoxaline]

Absolute Configuration

¹H-NMR (CDCl₃) δppm: 1.05-1.91 (15H, m), 2.15-2.30 (3H, m), 2.69 (1H, d,J=12.2 Hz), 3.01 (1H, d, J=12.2 Hz).

Reference Example 54 Production of (4aS,8aR)-tert-butyl4-benzyldecahydroquinoxaline-1-carboxylate

Absolute Configuration

Di-tert-butyl dicarbonate (1.70 g, 7.79 mmol) was added to a MeOH (16ml) solution of (4aR,8aS)-1-benzyldecahydroquinoxaline (1.63 g, 7.08mmol), and the mixture was stirred at room temperature for 2 hours. Thesolvent was distilled off, and the residue was then purified by basicsilica gel column chromatography (Hex-AcOEt) to obtain(4aS,8aR)-tert-butyl 4-benzyldecahydroquinoxaline-1-carboxylate (2.38 g,yield: quantitative) in a colorless oil form.

¹H-NMR (CDCl₃) δppm: 1.26-1.66 (14H, m), 1.79-1.96 (2H, m), 2.14-2.33(2H, m), 2.40-2.45 (1H, m), 2.66 (1H, brs), 2.86 (1H, d, J=13.2 Hz),3.03 (1H, brs), 3.50-4.10 (2H, br), 4.16 (1H, d, J=13.2 Hz), 7.21-7.36(5H, m).

A compound of Reference Example 55 below was produced in the same way asin Reference Example 54 using appropriate starting materials

Reference Example 55 (4aR,8aS)-tert-butyl4-benzyldecahydroquinoxaline-1-carboxylate

Absolute Configuration

¹H-NMR (CDCl₃) δppm: 1.26-1.66 (14H, m), 1.79-1.96 (2H, m), 2.14-2.33(2H, m), 2.40-2.45 (1H, m), 2.65 (1H, brs), 2.86 (1H, d, J=13.2 Hz),3.03 (1H, brs), 3.51-4.10 (2H, br), 4.16 (1H, d, J=13.2 Hz), 7.21-7.36(5H, m).

Reference Example 56 Production process of (4aS,8aR)-tert-butyldecahydroquinoxaline-1-carboxylate

Absolute Configuration

Pearlman's catalyst (0.24 g) was added to an EtOH (25 ml) solution of(4aS,8aR)-tert-butyl 4-benzyldecahydroquinoxaline-1-carboxylate (2.4 g,7.26 mmol). This suspension was stirred at room temperature for 1 hourin a hydrogen atmosphere. The catalyst was filtered through celite, andthe residue was washed with EtOH. Then, the filtrate was concentratedunder reduced pressure to obtain (4aS,8aR)-tert-butyldecahydroquinoxaline-1-carboxylate (1.67 g, yield: 96%) in a colorlessoil form.

¹H-NMR (CDCl₃) δppm: 1.16-1.53 (14H, m), 1.53-1.82 (3H, m), 1.83-2.00(1H, m), 2.68-2.83 (1H, m), 2.85-3.10 (3H, m), 3.65-4.06 (2H, m).

A compound of Reference Example 57 below was produced in the same way asin Reference Example 56 using appropriate starting materials.

Reference Example 57 (4aR,8aS)-tert-butyldecahydroquinoxaline-1-carboxylate

Absolute Configuration

¹H-NMR (CDCl₃) δppm: 1.18-1.55 (14H, m), 1.55-1.82 (3H, m), 1.85-2.00(1H, m), 2.68-2.82 (1H, m), 2.85-3.10 (3H, m), 3.65-4.04 (2H, m).

Reference Example 58 Production process of cis tert-butyl4-(4-chlorophenyl)decahydroquinoxaline-1-carboxylate

Relative Configuration

A toluene (4 ml) suspension of cis tert-butyldecahydroquinoxaline-1-carboxylate (240 mg, 0.999 mmol),1-bromo-4-chlorobenzene (211 mg, 1.10 mmol), Pd(OAc)₂ (11.2 mg, 0.0499mmol), t-Bu₃P.HBF₄ (14.5 mg, 0.0500 mmol), and NaOt-Bu (135 mg, 1.40mmol) was stirred for 5 hours under reflux in a nitrogen atmosphere. Thereaction solution was cooled to room temperature. Then, water (0.5 mL)and AcOEt (10 mL) were added thereto, and the mixture was stirred. MgSO₄was further added thereto, and the mixture was stirred. Insoluble matterwas filtered through celite, and the celite layer was washed with AcOEt(5 ml×2). Then, the filtrate was concentrated under reduced pressure.The obtained residue was purified by basic silica gel columnchromatography (Hex-AcOEt) to obtain a white solid (87 mg, yield: 25%).

¹H-NMR (CDCl₃) δppm: 1.10-1.40 (4H, m), 1.40-1.52 (10H, m), 1.63-1.71(1H, m), 1.73-1.82 (1H, m), 2.15-2.28 (1H, m), 2.74 (1H, dt, J=3.6, 11.8Hz), 2.90-2.97 (1H, m), 3.05-3.11 (1H, m), 3.27 (1H, dt, J=3.4, 12.6Hz), 3.77-3.86 (1H, m), 4.01-4.10 (1H, m), 7.08-7.13 (2H, m), 7.25-7.30(2H, m).

Compounds of Reference Examples 59 to 63 below were produced in the sameway as in Reference Example 35 using appropriate starting materials.

Reference Example 59 (4aS,8aS)-decahydroquinoxaline

Absolute Configuration

¹H-NMR (CDCl₃) δppm: 1.12-1.58 (6H, m), 1.62-1.78 (4H, m), 2.20-2.29(2H, m), 2.82-3.02 (4H, m).

Reference Example 60 (4aR,8aR)-decahydroquinoxaline

Absolute Configuration

¹H-NMR (CDCl₃) δppm: 1.14-1.27 (2H, m), 1.27-1.57(4H, m), 1.62-1.79 (4H,m), 2.19-2.30(2H, m), 2.83-3.03(4 H,m).

Reference Example 61 (2R,4aS,8aS)-2-methyldecahydroquinoxaline

Absolute Configuration

¹H-NMR (CDCl₃) δppm: 1.02 (3H, d, J=6.3 Hz), 1.11-1.51 (6H, m),1.62-1.79 (4H, m), 2.14-2.22 (1H, m), 2.24-2.33 (1H, m), 2.44 (1H, dd,J=10.2, 11.7 Hz), 2.81-2.91 (1H, m), 2.94 (1H, dd, J=2.9, 11.7 Hz).

Reference Example 62 (2S,4aR,8aR)-2-methyldecahydroquinoxaline

Absolute Configuration

¹H-NMR (CDCl₃) δppm: 1.02 (3H, d, J=6.3 Hz), 1.10-1.49 (6H ,m),1.62-1.80 (4H, m), 2.14-2.22 (1H, m), 2.24-2.33 (1H, m), 2.44 (1H, dd,J=10.3, 11.7 Hz), 2.80-2.91 (1H, m), 2.94 (1H, dd, J=2.9, 11.7 Hz).

Reference Example 63 (2R,4aS,8aS)-2-ethyldecahydroquinoxaline

Absolute Configuration

¹H-NMR (CDCl₃) δppm: 0.92 (3H, t, J=7.5 Hz), 1.1-1.55 (8H, m), 1.6-1.8(4H, m), 2.14-2.32 (2H, m), 2.39-2.5 (1H, m), 2.57-2.68 (1H, m), 3.01(1H, dd, J=2.6, 11.6 Hz).

Example 1 Production of(4aR,8aS)-3,3-dimethyl-1-(1-(triisopropylsilyl)-1H-indol-6-yl)decahydroquinoxaline

Absolute Configuration

A toluene (8 mL) suspension of(4aS,8aR)-2,2-dimethyldecahydroquinoxaline (337 mg, 2.00 mmol),6-bromo-1-(triisopropylsilyl)-1H-indole (846 mg, 2.40 mmol), sodiumtert-butoxide (269 mg, 2.80 mmol), palladium (II) acetate (22.5 mg,0.0902 mmol), and tri-tert-butylphosphine tetrafluoroborate (29.1 mg,0.101 mmol) was stirred for 5 hours under reflux in a nitrogenatmosphere. The reaction mixture was cooled to room temperature. Then,water (0.5 mL) and ethyl acetate (10 mL) were added thereto, and themixture was stirred, followed by addition of magnesium sulfate.Insoluble matter was filtered through celite, and the filtrate was thenconcentrated under reduced pressure. The obtained residue was purifiedby NH-silica gel column chromatography (n-hexane:ethyl acetate) toobtain colorless, amorphous(4aR,8aS)-3,3-dimethyl-1-(1-(triisopropylsilyl)-1H-indol-6-yl)decahydroquinoxaline(0.75 g, yield: 85%).

¹H-NMR(CDCl₃)δppm: 1.1-1.2 (18H, m), 1.21 (3H, s), 1.29 (3H, s),1.3-1.55 (5H, m), 1.55-1.8 (7H, m), 2.79 (1H, d, J=11.6 Hz), 2.91 (1H,d, J=11.6 Hz), 3.45-3.6 (2H, m), 6.49 (1H, dd, J=0.7, 3.2 Hz), 6.82 (1H,dd, J=2.0, 8.6 Hz), 6.93 (1H, s), 7.08 (1H, d, J=3.2 Hz), 7.45 (1H, d,J=8.6 Hz).

Example 2 Production of(4aR,8aS)-1-(1H-indol-6-yl)-3,3-dimethyldecahydroquinoxaline

Absolute Configuration

Tetra-n-butyl ammonium fluoride (1 M in THF) (3.41 mL, 3.41 mol) wasadded to a tetrahydrofuran (15 mL) solution of(4aR,8aS)-3,3-dimethyl-1-(1-(triisopropylsilyl)-1H-indol-6-yl)decahydroquinoxaline(0.750 g, 1.71 mmol) with stirring at room temperature, and the mixturewas stirred at room temperature for 1 hour. The solvent was distilledoff from the reaction mixture under reduced pressure. The obtainedresidue was purified by NH-silica gel column chromatography (ethylacetate/hexane) to obtain a white solid. The obtained solid wasrecrystallized from diisopropyl ether/hexane to obtain(4aR,8aS)-1-(1H-indol-6-yl)-3,3-dimethyldecahydroquinoxaline (305 mg,yield: 63%).

¹H-NMR(CDCl₃)δppm: 1.0-1.55 (1H, m), 1.55-1.85 (4H, m), 2.79 (1H, d,J=11.6 Hz), 2.94 (1H, d, J=11.6 Hz), 3.45-3.55 (1H, m), 3.6-3.75 (1H,m), 6.35-6.5 (1H, m), 6.79(1H, s), 6.86 (1H, dd, J=2.1, 8.7 Hz), 7.03(1H, dd, J=2.7, 2.7 Hz), 7.47 (1H, d, J=8.6 Hz), 7.92 (1H, br).

Example 3 Production of (4aS,8aS)-1-(4-chlorophenyl)decahydroquinoxaline

Absolute Configuration

1-chloroethyl chloroformate (229 μL, 2.10 mmol) was added to a methylenechloride (6.5 mL) solution of(4aS,8aS)-1-benzyl-4-(4-chlorophenyl)decahydroquinoxaline (0.650 g, 1.91mmol) with ice-cooling and stirring. The mixture was stirred at roomtemperature for 15 hours, and the reaction mixture was then concentratedunder reduced pressure. The obtained residue was dissolved in methanol(6.5 mL), and this solution was stirred for 1 hour under reflux. Thesolvent was distilled off from the reaction mixture. To the obtainedresidue, acetone (5 mL) was added, and the mixture was stirred. Thedeposited crystal was collected by filtration. The obtained crystal waswashed with acetone (1 mL) and then dried to obtain(4aS,8aS)-1-(4-chlorophenyl)decahydroquinoxaline (253 mg, yield: 53%) ina white powder form.

¹H-NMR(DMSO-d₆)δppm: 0.85-1.05 (1H, m), 1.1-1.4 (2H, m), 1.4-1.65 (3H,m), 1.65-1.8 (1H, m), 1.9-2.05 (1H, m), 2.8-3.0 (2H, m), 3.05-3.2 (3H,m), 3.2-3.5 (1H, m), 7.1-7.2 (2H, m), 7.35-7.45 (2H, m), 9.2-9.65 (2H,m).

Example 4 Production ofcis-4-(benzo[b]thiophen-5-yl)-1,2,2-trimethyldecahydroquinoxalinehydrochloride

Relative Configuration

A 37% aqueous formaldehyde solution (0.81 mL, 9.9 mmol) was added to amethanol (10 mL) solution ofcis-1-(benzo[b]thiophen-5-yl)-3,3-dimethyldecahydroquinoxaline (298 mg,0.992 mmol) with stirring at room temperature. After 30 minutes, sodiumcyanoborohydride (311 mg, 4.96 mmol) and acetic acid (0.30 mL) wereadded to the reaction solution at room temperature, and the mixture wasstirred overnight. The solvent was distilled off from the reactionmixture under reduced pressure. Then, a saturated aqueous solution ofsodium bicarbonate (50 mL) was added thereto, followed by extractionwith ethyl acetate (50 mL) twice. The organic layer was washed withwater twice and with saturated saline once, then dried over magnesiumsulfate, and concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (methylenechloride:methanol=10:1) to obtain a brown oil. 4 N hydrochloricacid/ethyl acetate (0.6 mL) was added to an ethanol solution of theobtained oil with stirring at room temperature, and the depositedcrystal was collected by filtration. The obtained crystal was washedwith ethyl acetate and then dried under reduced pressure to obtaincis-4-(benzo[b]thiophen-5-yl)-1,2,2-trimethyldecahydroquinoxalinehydrochloride (258 mg, yield: 74%) in a white powder form.

¹H-NMR(CDCl₃)δppm: 1.17-1.34 (1H, m), 1.37-1.74 (2H, m), 1.47 (3H, s),1.87-2.04 (1H, m), 1.90 (3H, s), 2.20-2.30 (1H, m), 2.39-2.54 (1H, m),2.64-2.88 (2H, m), 2.75 (3H, d, J=4.9 Hz), 3.12 (1H, d, J=13.2 Hz),3.69-3.74 (1H, m), 3.85-3.93 (1H, m), 3.87 (1H, d, J=13.2 Hz), 7.01 (1H,dd, J=8.8, 2.3 Hz), 7.21-7.32 (2H, m), 7.44 (1H, d, J=5.4 Hz), 7.75 (1H,d, J=8.8 Hz), 11.20 (1H, brs).

Example 5 Production of2-(trans-4-(naphthalen-2-yl)decahydroquinoxalin-1-yl)ethanoldihydrochloride

Relative Configuration

Tetra-n-butyl ammonium fluoride (1 M in THF) (2.1 mL, 2.1 mmol) wasadded to a THF (10 mL) solution oftrans-1-(2-(tert-butyldimethylsilyloxy)ethyl)-4-(naphthalen-2-yl)decahydroquinoxaline(820 mg, 1.93 mmol) with stirring at room temperature, and the mixturewas stirred overnight. To the reaction mixture, ethyl acetate was added,and the resultant mixture was washed with water twice and with saturatedsaline once, then dried over magnesium sulfate, and concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (methylene chloride:methanol=10:1) to obtain a colorless,amorphous solid (534 mg). A 319 mg aliquot of the obtained solid wasdissolved in ethanol. To the solution, 4 N hydrochloric acid/ethylacetate (1.0 mL) was added with stirring at room temperature, and thedeposited crystal was collected by filtration. The obtained crystal waswashed with ethyl acetate and then dried under reduced pressure toobtain 2-(trans-4-(naphthalen-2-yl)decahydroquinoxalin-1-yl)ethanoldihydrochloride (365 mg, yield: 49%) in a white powder form.

¹H-NMR(CDCl₃)δppm: 1.23-1.76 (4H, m), 1.86-2.08 (3H, m),2.43-2.48 (1H,m), 3.18-3.25 (1H, m), 3.72-3.77 (2H, m), 3.93-3.98 (1H, m), 3.93-4.78(1H, br), 4.08-4.20 (2H, m), 4.39-4.55 (1H, m), 4.57-4.78 (2H, m),4.97-5.06 (1H, m), 7.61-7.68 (3H, m), 7.81-8.07 (3H, m), 8.17-8.69 (1H,br), 12.73 (1H, brs), 14.91 (1H, brs).

Example 77 Production of(4aS,8aR)-1-(7-fluorobenzofuran-4-yl)-3,3-dimethyldecahydroquinoxaline

Absolute Configuration

A toluene (4 ml) suspension of(4aR,8aS)-2,2-dimethyldecahydroquinoxaline (168 mg, 0.998 mmol),4-bromo-7-fluorobenzofuran (258 mg, 1.20 mmol), Pd(OAc)₂ (11.2 mg,0.0499 mmol), t-Bu₃P.HBF₄ (14.5 mg, 0.0500 mmol), and NaOt-Bu (135 mg,1.40 mmol) was stirred for 4 hours under reflux in a nitrogenatmosphere. The reaction solution was cooled to room temperature. Then,water (0.5 mL) and AcOEt (10 mL) were added thereto, and the mixture wasstirred. MgSO₄ was further added thereto, and the mixture was stirred.Insoluble matter was filtered, and the residue was washed with AcOEt (5ml×2) Then, the filtrate was concentrated under reduced pressure. Theobtained residue was purified by basic silica gel column chromatography(Hex-AcOEt) to obtain a colorless oil (167 mg). This oil wascrystallized from hexane (1 mL) to obtain(4aS,8aR)-1-(7-fluorobenzofuran-4-yl)-3,3-dimethyldecahydroquinoxaline(107 mg, yield: 35%) in a white powder form.

¹H-NMR (CDCl₃) δppm: 1.0-1.45 (11H, m), 1.6-1.8 (3H, m), 1.8-1.95 (1H,m), 2.70 (1H, d, J=11.3 Hz), 3.04 (1H, d, J=11.3 Hz), 3.50 (1H, ddd,J=3.8, 3.8, 12.1 Hz), 3.55-3.65 (1H, m), 6.47 (1H, dd, J=3.4, 8.6 Hz),6.84 (1H, dd, J=2.5, 2.5 Hz), 6.89 (1H, dd, J=8.6, 10.4 Hz), 7.60 (1H,d, J=2.2 Hz).

Example 106 Production of(4aS,8aR)-1-(4-chlorophenyl)-3,3-dimethyldecahydroquinoxalinehydrochloride

Absolute Configuration

A toluene (10 ml) suspension of(4aR,8aS)-2,2-dimethyldecahydroquinoxaline (252 mg, 1.50 mmol),1-bromo-4-chlorobenzene (345 mg, 1.80 mmol), Pd(OAc)₂ (16.8 mg, 0.0748mmol), t-Bu₃P.HBF₄ (21.8 mg, 0.0751 mmol), and NaOt-Bu (202 mg, 2.10mmol) was stirred for 5 hours under reflux in a nitrogen atmosphere. Thereaction solution was cooled to room temperature. Then, water (0.5 mL)and AcOEt (10 mL) were added thereto, and the mixture was stirred. MgSO₄was further added thereto, and the mixture was stirred. Then, insolublematter was filtered through celite. The filtrate was concentrated underreduced pressure, and the obtained residue was purified by basic silicagel column chromatography (Hex-AcOEt). The obtained oil was dissolved in1 N HCl-EtOH (3 mL), and the solvent was distilled off under reducedpressure. The deposited crystal was recrystallized from ethanol/acetoneto obtain (4aS,8aR)-1-(4-chlorophenyl)-3,3-dimethyldecahydroquinoxalinehydrochloride (262 mg, yield: 55%) in a white powder form.

¹H-NMR (DMSO-d₆) δppm: 1.2-1.45 (6H, m), 1.51 (3H, s), 1.6-2.1 (5H, m),2.93 (1H, d, J=13.6 Hz), 3.40 (1H, d, J=13.8 Hz), 3.65-3.85 (1H, m),3.9-4.1 (1H, m), 6.8-7.05 (2H, m), 7.1-7.35 (2H, m), 8.14 (1H, br), 9.77(1H, br).

Example 112 Production of(4aS,8aR)-1(3-chloro-4-fluorophenyl)-3,3-dimethyldecahydroquinoxalinehydrochloride

Absolute Configuration

A toluene (10 ml) suspension of(4aR,8aS)-2,2-dimethyldecahydroquinoxaline (168 mg, 0.998 mmol),4-bromo-2-chloro-1-fluorobenzene (251 mg, 1.20 mmol), Pd(OAc)₂ (11.2 mg,0.0500 mmol), t-Bu₃P.HBF₄ (14.5 mg, 0.0500 mmol), and NaOt-Bu (135 mg,1.40 mmol) was stirred for 5 hours under reflux in a nitrogenatmosphere. The reaction solution was cooled to room temperature. Then,water (0.5 mL) and AcOEt (10 mL) were added thereto, and the mixture wasstirred. MgSO₄ was further added thereto, and the mixture was stirred.Then, insoluble matter was filtered. The filtrate was concentrated underreduced pressure, and the obtained residue was purified by basic silicagel column chromatography (Hex-AcOEt). The obtained oil was dissolved in1 N HCl-EtOH (3 mL), and ethanol was distilled off under reducedpressure. The deposited crystal was recrystallized from ethanol/acetoneto obtain(4aS,8aR)-1-(3-chloro-4-fluorophenyl)-3,3-dimethyldecahydroquinoxalinehydrochloride (153 mg, yield: 46%) in a white powder form.

¹H-NMR (DMSO-d₆) δppm: 1.15-1.45 (6H, m), 1.51 (3H, s), 1.6-1.9 (4H, m),1.9-2.05 (1H, m), 2.94 (1H, d, J=13.5 Hz), 3.3-3.45 (1H, m), 3.65-3.8(1H, m), 3.95-4.1 (1H, m), 6.85-7.0 (1H, m), 7.12 (1H, dd, J=3.0, 6.2Hz), 7.25 (1H, dd, J=9.1, 9.1 Hz), 8.13 (1H, br), 9.86 (1H, br).

Example 150 Production of5-((4aR,8aS)-3,3-dimethyldecahydroquinoxalin-1-yl)-1-methyl-1H-indole-2-carbonitrile

Absolute Configuration

A toluene (4 ml) suspension of(4aS,8aR)-2,2-dimethyldecahydroquinoxaline (168 mg, 0.998 mmol),5-bromo-1-methyl-1H-indole-2-carbonitrile (259 mg, 1.10 mmol), Pd(OAc)₂(11.2 mg, 0.0499 mmol), t-Bu₃P.HBF₄ (14.5 mg, 0.0500 mmol), and NaOt-Bu(135 mg, 1.40 mmol) was stirred for 4 hours under reflux in a nitrogenatmosphere. The reaction solution was cooled to room temperature. Then,water (0.5 mL) and AcOEt (10 mL) were added thereto, and the mixture wasstirred. MgSO₄ was further added thereto, and the mixture was stirred.Insoluble matter was filtered through celite, and the residue was washedwith CH₂Cl₂:MeOH (3:1) (5 mL×2). Then, the filtrate was concentratedunder reduced pressure. The obtained residue was purified by basicsilica gel column chromatography (Hex-AcOEt) to obtain a colorless oil.This oil was crystallized from hexane (1 mL) to obtain(4aS,8aR)-1-(7-fluorobenzofuran-4-yl)-3,3-dimethyldecahydroquinoxaline(148 mg, yield: 46%) in a pale yellow powder form.

¹H-NMR (CDCl₃) δppm: 0.7-2.3 (15H, m), 2.7-3.2 (2H, m), 3.5-3.8 (2H, m),3.85 (3H, s), 6.95-7.05 (2H, m), 7.15-7.3 (2H, m).

Example 237 Production of(4aS,8aS)-1-(3-chloro-4-cyanophenyl)-3,3-dimethyldecahydroquinoxalinehydrochloride

Absolute Configuration

A toluene (10 ml) suspension of(4aS,8aS)-2,2-dimethyldecahydroquinoxaline (400 mg, 2.38 mmol),4-bromo-2-chlorobenzonitrile (669 mg, 3.09 mmol), Pd(OAc)₂ (53 mg, 0.24mmol), t-Bu₃P.HBF₄ (70 mg, 0.24 mmol), and t-BuONa (320 mg, 3.33 mmol)was stirred for 5 hours under reflux in a nitrogen atmosphere. Thereaction solution was cooled. Then, insoluble matter was filteredthrough celite, and the filtrate was concentrated. The obtained residuewas purified by silica gel column chromatography (CH₂Cl₂/MeOH) to obtainan orange amorphous solid. This amorphous solid was dissolved in ethylacetate (5 mL). A crystal deposited by the addition of 4 N HCl/AcOEt(0.6 mL) was collected by filtration and dried under reduced pressure toobtain(4aS,8aS)-1-(3-chloro-4-cyanophenyl)-3,3-dimethyldecahydroquinoxaline(304 mgm, 48%) in a pale orange powder form.

¹H-NMR (CDCl₃) δppm: 1.05-1.20 (1H, m), 1.23-1.44 (2H, m), 1.54-2.10(4H, m), 1.63 (3H, s), 1.68 (3H, s), 2.35-2.40 (1H, m), 2.89 (1H, d,J=12.7 Hz), 3.19 (2H, br), 3.34 (1H, d, J=12.7 Hz), 7.06 (1H, dd, J=8.4,2.0 Hz), 7.20 (1H, d, J=2.0 Hz), 7.61 (1H, d, J=8.4 Hz), 9.62 (1H, brs),9.90 (1H, br)

Example 579 Production of(4a′R,8a′S)-4′-(7-methoxybenzofuran-4-yl)octahydro-1′H-spiro[cyclobutane-1,2′-quinoxaline]

Absolute Configuration

A toluene (4 ml) suspension of(4a′R,8a′S)-octahydro-1′H-spiro[cyclobutane-1,2′-quinoxaline] (180 mg,0.998 mmol), 4-bromo-7-methoxybenzofuran (250 mg, 1.10 mmol), Pd(OAc)₂(11.2 mg, 0.0499 mmol), t-Bu₃P.HBF₄ (14.5 mg, 0.0500 mmol), and NaOt-Bu(135 mg, 1.40 mmol) was stirred for 4 hours under reflux in a nitrogenatmosphere. The reaction solution was cooled to room temperature. Then,water (0.5 mL) and AcOEt (10 mL) were added thereto, and the mixture wasstirred. MgSO₄ was further added thereto, and the mixture was stirred.Insoluble matter was filtered, and the residue was washed with AcOEt (5mL×2). Then, the filtrate was concentrated under reduced pressure. Theobtained residue was purified by basic silica gel column chromatography(Hex-AcOEt) to obtain a colorless amorphous solid. This solid wascrystallized from hexane (1 mL) to obtain(4a′R,8a′S)-4′-(7-methoxybenzofuran-4-yl)octahydro-1′H-spiro[cyclobutane-1,2′-quinoxaline](107 mg, yield: 35%) in a white powder form.

¹H-NMR (CDCl₃) δppm: 0.95-1.1 (2H, m), 1.3-1.4 (1H, m), 1.4-2.1 (1H, m),2.25-2.4 (1H, m), 3.01 (1H, d, J=11.0 Hz), 3.17 (1H, d, J=11.1 Hz), 3.40(1H, br), 3.45-3.5 (1H, m), 3.97 (3H, s), 6.58 (1H, d, J=8.4 Hz), 6.70(1H, d, J=8.4 Hz), 6.80 (1H, d, J=2.1 Hz), 7.58 (1 H,d,J=2.1 Hz).

Example 580 Production of(4aS,8aR)-1-(6,7-difluorobenzofuran-4-yl)-3,3-dimethyldecahydroquinoxalinehydrochloride

Absolute Configuration

A toluene (6 ml) suspension of(4aR,8aS)-2,2-dimethyldecahydroquinoxaline (252 mg, 1.50 mmol),4-bromo-6,7-difluorobenzofuran (384 mg, 1.65 mmol), Pd(OAc)₂ (16.8 mg,0.0748 mmol), t-Bu₃P.HBF₄ (21.8 mg, 0.0751 mmol), and NaOt-Bu (202 mg,2.10 mmol) was stirred for 3 hours under reflux in a nitrogenatmosphere. The reaction solution was cooled to room temperature. Then,water (0.5 mL) and AcOEt (10 mL) were added thereto, and the mixture wasstirred. MgSO₄ was further added thereto, and the mixture was stirred.Then, insoluble matter was filtered through celite. The filtrate wasconcentrated under reduced pressure, and the obtained residue waspurified by basic silica gel column chromatography (Hex-AcOEt) to obtaina pale yellow oil (193 mg). This oil was dissolved in ethanol (2 mL). Tothe solution, 1 N HCl-EtOH (1.2 mL) was added, and the mixture wasstirred. The deposited crystal was collected by filtration, washed withethyl acetate, and then dried under reduced pressure to obtain(4aS,8aR)-1-(6,7-difluorobenzofuran-4-yl)-3,3-dimethyldecahydroquinoxalinehydrochloride (167 mg, yield: 31%) in a white powder form.

¹H-NMR (DMSO-d₆) δppm: 1.01-1.17 (2H, m), 1.34-1.44 (1H, m), 1.48 (3H,s), 1.52 (3H, s), 1.59-2.07 (5H, m), 3.00 (1H, d, J=13.0 Hz), 3.28 (1H,d, J=13.2 Hz), 3.75-3.9 (1H, m), 4.0-4.15 (1H, m), 6.83 (1H, dd, J=5.9,13.5 Hz), 7.36 (1H, dd, J=2.6, 2.6 Hz), 8.0-8.2 (2H, m), 9.7-9.9 (1H,m).

Example 581 Production of(4aS,8aS)-1-(2-cyano-1-(triisopropylsilyl)-1H-indol-5-yl)3,3-dimethyldecahydroquinoxaline

Absolute Configuration

A toluene (5 ml) suspension of(4aS,8aS)-2,2-dimethyldecahydroquinoxaline (200 mg, 1.19 mmol),5-bromo-1-(triisopropylsilyl)-1H-indole-2-carbonitrile (493 mg, 1.31mmol), Pd(OAc)₂ (13.3 mg, 0.0594 mmol), tBu₃P.HBF₄ (17.2 mg, 0.0594mmol), and t-BuONa (137 mg, 1.43 mmol) was stirred at 100° C. for 4hours in a nitrogen atmosphere. Insoluble matter was filtered throughcelite, and the filtrate was concentrated. The obtained residue waspurified by basic silica gel column chromatography (AcOEt/hexane) toobtain (4aS,8aS)-1-(2-cyano-1-(triisopropylsilyl)-1H-indol-5-yl)3,3-dimethyldecahydroquinoxaline (430 mg, 78%) in a white amorphoussolid form.

¹H-NMR (CDCl₃) δppm: 0.75-1.38 (26H, m), 1.41 (3H, s), 1.54-1.77 (4H,m), 2.01 (3H, quintet, J=7.5 Hz), 2.25-2.32 (1H, m), 2.65 (1H, d, j=11.2Hz), 2.75-2.85 (2H, m), 7.11 (1H, dd, J=2.0, 9.1 Hz), 7.32 (1H, d, J=2.0Hz), 7.33 (1H, d, J=0.5 Hz), 7.50 (1H, d, J=9.1 Hz).

Example 582 Production of (4aS,8aS)-1-(2-cyano-1H-indol-5-yl)3,3-dimethyldecahydroquinoxaline

Absolute Configuration

Tetrabutylammonium fluoride (1 M THF solution, 0.73 mL, 0.73 mmol) was1.5 added to an anhydrous tetrahydrofuran (5 mL) solution of(4aS,8aS)-1-(2-cyano-1-(triisopropylsilyl)-1H-indol-5-yl)3,3-dimethyldecahydroquinoxaline (170 mg, 0.366 mmol) at roomtemperature, and the reaction solution was stirred at room temperaturefor 1 hour. The reaction solution was concentrated under reducedpressure, and the obtained residue was purified by basic silica gelcolumn chromatography (AcOEt/hexane=1/10→1/1). The solvent was removedunder reduced pressure. The obtained residue was recrystallized fromethyl acetate/n-hexane to obtain (4aS,8aS)-1-(2-cyano-1H-indol-5-yl)3,3-dimethyldecahydroquinoxaline (30 mg, yield: 27%) in a white powderform.

¹H-NMR (DMSO-d₆) δppm: 0.82-1.00 (4H, m), 1.08-1.34 (6H, m), 1.42-1.67(5H, m), 2.19-2.27 (1H, m), 2.55 (1H, d, J=10.9 Hz), 2.59-2.69 (2H, m),7.11 (1H, dd, J=1.8, 8.8 Hz), 7.26 (1H, d, J=0.8 Hz), 7.32 (1H, d, J=1.8Hz), 7.36 (1H, d, J=8.8 Hz) 12.25 (1H, brs).

Example 583 Production of(4aS,8aR)-1-(7-chloro-2,3-dihydro-1H-inden-4-yl)-3,3-dimethyldecahydroquinoxaline

Absolute Configuration

A toluene (1 mL) solution of bis(tri-tert-butylphosphine)palladium (25.6mg, 0.0501 mmol) was added to a toluene (4 ml) suspension of(4aR,8aS)-2,2-dimethyldecahydroquinoxaline (168 mg, 0.998 mmol),4-bromo-7-chloro-2,3-dihydro-1H-indene (255 mg, 1.10 mmol), and NaOt-Bu(135 mg, 1.40 mmol), and the mixture was stirred for 4 hours underreflux in a nitrogen atmosphere. The reaction solution was cooled toroom temperature. Then, water (0.5 mL) and AcOEt (10 mL) were addedthereto, and the mixture was stirred. MgSO₄ was further added thereto,and the mixture was stirred. Insoluble matter was filtered throughcelite, and the residue was washed with AcOEt (5 mL×2). Then, thefiltrate was concentrated under reduced pressure. The obtained residuewas purified by basic silica gel column chromatography (Hex-AcOEt) toobtain a white solid (167 mg). This solid was recrystallized fromethanol/water to obtain(4aS,8aR)-1-(7-chloro-2,3-dihydro-1H-inden-4-yl)-3,3-dimethyldecahydroquinoxaline(136 mg, yield: 43%) in a white powder form.

¹H-NMR (CDCl₃) δppm: 0.97-1.12 (3H, m), 1.16 (3H, s), 1.27 (3H, s),1.31-1.44 (2H, m), 1.45-1.76 (3H, m), 1.78-1.92 (1H, m), 1.94-2.06 (1H,m), 2.12-2.23 (1H, m), 2.51 (1H, d, J=11.2 Hz), 2.85-3.05 (5H, m),3.1-3.2 (1H, m), 3.45-3.55 (1H, m), 6.58 (1H, d, J=8.4 Hz), 7.03 (1H, d,J=8.4 Hz).

Example 584 Production of(4aS,8aS)-1-(6-cyanonaphthalen-2-yl)-3,3-dimethyldecahydroquinoxalinedihydrochloride

Absolute Configuration

A toluene (5 mL) suspension of(4aR,8aS)-2,2-dimethyldecahydroquinoxaline (200 mg, 1.19 mmol),6-bromo-2-naphthonitrile (303 mg, 1.31 mmol), Pd(OAc)₂ (13.3 mg, 0.0594mmol), tBu₃P.HBF₄ (17.2 mg, 0.0594 mmol), and t-BuONa (137 mg, 1.43mmol) was stirred at 100° C. for 4 hours. Insoluble matter was filteredthrough celite, and the filtrate was concentrated. The obtained residuewas purified by basic silica gel column chromatography (AcOEt/hexane).The solvent was removed under reduced pressure. The obtained residue wasdissolved in ethyl acetate. To this solution, 1 N hydrochloricacid-ethanol was added, and the deposited crystal was collected byfiltration. The obtained crystal was dried under reduced pressure toobtain(4aS,8aS)-1-(6-cyanonaphthalen-2-yl)-3,3-dimethyldecahydroquinoxalinedihydrochloride (303 mg, yield: 65%) in a white powder form.

¹H-NMR (DMSO-d₆) δppm: 1.10-1.50 (6H, m), 1.56-1.90 (1H, m), 2.00-2.14(1H, m), 3.08-3.45 (4H, m), 4.68-5.32 (1H, br), 7.45 (1H, dd, J=2.0, 8.9Hz), 7.64 (1H, d, J=1.8 Hz), 7.73 (1H, dd, J=1.6, 8.6 Hz), 8.00 (1H, d,J=8.6 Hz), 8.04 (1H, d, J=8.6 Hz), 8.49 (1H, s), 9.10-9.28 (1H, br),10.04-10.28 (1H, br).

Example 585 Production of(4aS,8aS)-3,3-dimethyl-1-(1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)decahydroquinoxaline

Absolute Configuration

A toluene (5 mL) suspension of(4aS,8aS)-2,2-dimethyldecahydroquinoxaline (200 mg, 1.19 mmol),4-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (462 mg, 1.31mmol), Pd(OAc)₂ (13.3 mg, 0.0594 mmol), tBu₃P.HBF₄ (17.2 mg, 0.0594mmol), and t-BuONa (137 mg, 1.43 mmol) was stirred at 100° C. for 4hours in a nitrogen atmosphere. Insoluble matter was filtered throughcelite, and the filtrate was concentrated. The obtained residue waspurified by basic silica gel column chromatography (AcOEt/hexane) toobtain(4aS,8aS)-3,3-dimethyl-1-(1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)decahydroquinoxaline(439 mg, 84%) in a white amorphous solid form.

¹H-NMR (CDCl₃) δppm: 0.95-1.20 (22H, m), 1.36-1.45 (3H, m), 1.52 (3H,s), 1.65-1.92 (7H, m), 2.11-2.20 (1H, m), 2.57-2.67 (2H, m), 2.83-2.95(1H, m), 3.26-(1H, d, J=11.7 Hz), 6.55 (1H, d, J=3.5 Hz), 6.63 (1H, d,J=5.3 Hz), 7.18 (1H, d, J=3.5 Hz), 8.12 (1H, d, J=5.3 Hz).

Example 586 Production of(4aS,8aS)-3,3-dimethyl-1-(1H-pyrrolo[2,3-b]pyridin-4-yl)decahydroquinoxalinefumarate

Absolute Configuration

Tetrabutylammonium fluoride (1 M THF solution, 1.95 mL, 1.95 mmol) wasadded to an anhydrous tetrahydrofuran (5 mL) solution of(4aS,8aS)-3,3-dimethyl-1-(1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)decahydroquinoxaline(430 mg, 0.976 mmol), and the mixture was stirred at room temperaturefor 1 hour. The reaction solution was concentrated under reducedpressure, and the obtained residue was purified by basic silica gelcolumn chromatography (AcOEt/hexane=1/10→1/1) to obtain a product (370mg, 1.30 mmol) in an oil form. This oil was dissolved in ethanol (5 mL).To this solution, an ethanol (5 mL) solution of fumaric acid (151 mg)was added, and ethanol was removed under reduced pressure. The obtainedsolid was recrystallized from ethanol/ethyl acetate to obtain5-((4aS,8aS)-3,3-dimethyldecahydroquinoxalin-1-yl)-1H-indole-2-carbonitrile(246 mg, yield: 63%) in a white powder form.

¹H-NMR (DMSO-d₆) δppm: 0.94-1.09 (1H, m), 1.20 (3H, s), 1.26-1.55 (7H,m), 1.68-1.78 (1H, m), 1.85-2.04 (2H, m), 2.81-2.93 (1H, m), 2.95-3.23(3H, m), 6.36-6.42 (1H, m), 6.49 (2H, s), 6.71 (1H, d, J=5.2 Hz),7.32-7.38 (1H, m), 8.09 (1H, d, J=5.2 Hz), 8.50-11.20 (1H, br), 11.59(1H, s).

Example 587 Production of(4aS,8aS)-1-(4-(difluoromethoxy)-3-fluorophenyl)-3,3-dimethyldecahydroquinoxalinedihydrochloride

Absolute Configuration

A toluene (5 mL) suspension of(4aR,8aS)-2,2-dimethyldecahydroquinoxaline 1.5 (200 mg, 1.19 mmol),4-bromo-1-difluoromethoxy-2-fluorobenzene (315 mg, 1.31 mmol), Pd(OAc)₂(13.3 mg, 0.0594 mmol), tBu₃P.HBF₄ (17.2 mg, 0.0594 mmol), and t-BuONa(137 mg, 1.43 mmol) was stirred at 100° C. for 4 hours. Insoluble matterwas filtered through celite, and the filtrate was concentrated. Theobtained residue was purified by basic silica gel column chromatography(AcOEt/hexane). The solvent was removed under reduced pressure. Theobtained residue was dissolved in ethyl acetate. To this solution, 1 Nhydrochloric acid-ethanol was added, and the deposited crystal wascollected by filtration. The obtained crystal was dried under reducedpressure to obtain(4aS,8aS)-1-(4-difluoromethoxy-3-fluorophenyl)-3,3-dimethyldecahydroquinoxalinedihydrochloride (193 mg, yield: 40%) in a white powder form.

¹H-NMR (DMSO-d₆) δppm: 1.01-1.39 (6H, m), 1.49-1.67 (6H, m), 1.67-1.77(1H, m), 1.96-2.05 (1H, m), 2.81-2.95 (2H, m), 3.02 (1H, d, J=12.5 Hz),3.10-3.23 (1H, m), 4.30-4.80 (1H, br), 6.96-7.01 (1H, m), 7.02 (0.25H,s), 7.17 (1H, dd, J=2.5, 12.1 Hz), 7.20 (0.5H, s), 7.33 (1H, t, J=8.9Hz), 7.39 (0.25H, s), 9.04-9.21 (1H, m), 9.70-9.85 (1H, m).

Compounds of Examples 6 to 76, 78 to 105, 107 to 111, 113 to 149, 151 to236, 238 to 578, 588 to 1656 shown in tables below were produced in thesame way as in the Examples using corresponding appropriate startingmaterials. In these tables, for example, the produced compounds havephysical properties such as a crystalline form, m.p. (melting point),salt, ¹H-NMR, and MS (mass spectrum).

TABLE 1 Relative configuration

Exam- ple X R⁴ 1H-NMR Salt 6 —CH₃—

1H-NMR (DMSO-d6) δ ppm: 1.39 (3H, s), 1.49 (3H, s), 1.56-2.20 (6 H, m),3.04 (1H, d, J = 13.3 Hz), 3.61 (1H, d, J = 13.3 Hz), 3.75-3.90 (1H, m),4.40-4.55 (1 H, m), 7.17-7.30 (2 H, m), 7.33-7.45 (2 H, m), 7.65-7.63 (3H, m), 8.35-8.80 (1 H, brr), 9.70-9.95 (1 H, brr). Hydro- chloride 7—CH₃—

1H-NMR (DMSO-d6) δ ppm: 1.39 (3H, s), 1.48 (3H, s), 1.55-2.19 (5H, m),3.01 (1H, d, J = 13.2 Hz), 3.45 (1H, d, J = 13.2 Hz), 3.70-3.87 (1H, m),4.25-4.45 (1H, m), 7.17 (1H, dd, J = 2.2, 9.0 Hz), 7.29 (1H, d, J = 6.4Hz), 7.37 (1H, d, J = 2.2 Hz), 7.67 (1H, d, J = 6.4 Hz), 7.81 (1H, J=8.9 Hz), 8.42-8.65 (1H, br), 9.80-10.05 (1H, br). Hydro- chloride 8 —O—

1H-NMR (DMSO-d6) δ ppm: 1.42 (3H, s), 1.49 (3H, s), 3.07 (1H, d, J =13.4 Hz), 3.53 (1H, d, J = 13.4 Hz), 3.72 (1H, t, J = 8.6 Hz), 3.90-4.17(4H, m), 4.79-4.94 (1H, m), 7.19 (1H, dd, J = 2.4, 5.9 Hz), 7.30 (1H,dd, J = 0.5, 5.4 Hz), 7.41 (1H, d, J = 2.4 Hz), 7.69 (1H, d, J = 5.4Hz), 7.83 (1H, d, J = 6.9 Hz), 8.60-8.85 (1H, br), 10.41-10.65 (1H, br).Hydro- chloride 9 —CH₃—

1H-NMR (DMSO-d6) δ ppm: 1.33 (3H, s), 1.44 (3H, s), 1.55-2.19 (6H, m),2.92 (1H, d, J = 13.5 Hz), 3.45 (1H, d, J = 13.5 Hz), 3.68-3.82 (1H, m),4.20-4.35 (1H, m), 6.98 (2H, d, J = 9.0 Hz), 7.23 (2H, d, J = 9.0 Hz),8.40-8.86 (1H, br), 9.75-10.05 (1H, br). Hydro- chloride 10  —CH₃—

1H-NMR (DMSO-d6) δ ppm: 1.32 (3H, s), 1.43 (3H, s), 1.55-2.15 (6H, m),2.95 (1H, d, J = 13.6 Hz), 3.58 (1H, d, J = 13.8 Hz), 3.65-3.82 (1H, m),4.20-4.40 (1H, m), 5.97 (1H, dd, J = 2.9, 9.0 Hz), 7,19 (1H, d, J = 2.9Hz), 7.40 (1H, d, J = 9.0 Hz), 8.40-8.52 (1H, br), 9.70-9.95 (1H, br).Hydro- chloride 11  —O—

1H-NMR (DMSO-d6) δ ppm: 1.34 (3H, s), 1.44 (3H, s), 2.99 (1H, d, J =13.5 Hz), 3.50-3.73 (2H, m), 3.85-4.11 (4H, m), 4.71-4.90 (1H, m),6.95-7.08 (1H, m), 7.20-7.30 (1H, m), 7.42 (1H, d, J 9.0 Hz), 8.60-8.89(1H, br), 10.20-10.61 (1H, br). Hydro- chloride

TABLE 2 Relative configuration

Exam- ple X R⁴ NMR Salt 12 —CH₃—

1H-NMR (DMSO-d6) δ ppm: 1.30-1.50 (4H, m), 1.80 (3H, s), 1.55-2.05 (4H,m), 2.05-2.23 (1H, m), 2.82-2.96 (1H, m), 3.06-3.25 (1H, m), 3.25-3.45(2H, m), 4.00-5.25 (1H, br), 7.29 (1H, dd, J = 2.1, 8.8 Hz), 7.35-7.60(3H, m), 7.76-7.94 (3H, m), 9.29-9.57 (1H, br), 9.78-10.08 (1H, br).Dihydro- chloride 13 —CH₃—

1H-NMR (DMSO-d6) δ ppm: 1.30-1.50 (4H, m), 1.80 (3H, s), 1.55-2.07 (6H,m), 2.94 (1H, d, J = 12.4 Hz), 3.05-3.45 (3H, m), 4.40-5.88 (1H, br),7.18 (1H, dd, J = 1.7, 8.7 Hz), 7.42 (1H, d, J = 5.4 Hz), 7.55 (1H, d, J= 1.7 Hz), 7.76 (1H, d, J = 5.4 Hz), 7.93 (1H, d, J = 5.7 Hz), 9.40-9.70(1H, br), 9.80-10.12 (1H, br). Dihydro- chloride 14 —O—

1H-NMR (DMSO-d6) δ ppm: 1.44 (3H, s), 1.62 (3H, s), 2.90 (1H, d, J =12.7 Hz), 3.34 (1H, d, J = 12.7 Hz), 3.48-3.51 (2H, m), 3.75-9.95 (2H,m), 4.00-4.10 (1H, m), 4.11-4.28 (1H, m), 4.75-5.01 (1H, br), 7.12 (1H,dd, J = 2.1, 8.7 Hz), 7.40 (1H, d, J = 5.4 Hz), 7.62 (1H, d, J = 2.1Hz), 7.75 (1H, d, J = 5.4 Hz), 7.91 (1H, d, J = 5.7 Hz), 9.88-10.08 (1H,br), 10.08-10.80 (1H, br). Dihydro- chloride 15 —CH₃—

1H-NMR (DMSO-d6) δ ppm: 1.25-1.45 (4H, m), 1.52 (3H, s), 1.65-1.88 (3H,m), 1.88-2.10 (2H, m), 2.84 (1H, d, J = 12.8 Hz), 2.94-3.10 (1H, m),3.18-3.39 (2H, m), 4.03-4.70 (1H, br), 7.09 (1H, dd, J = 2.6, 6.7 Hz),7.33 (1H, d, J = 2.6 Hz), 7.52 (1H, d, J = 8.7 Hz), 9.25-9.83 (1H, br),9.72-10.04 (1H, br). Dihydro- chloride 16 —CH₃—

1H-NMR (DMSO-d6) δ ppm: 1.24-1.45 (4H, m), 1.56 (3H, s), 1.83-2.04 (6H,m), 2.82 (1H, d, J = 12.8 Hz), 2.90-3.08 (1H, m), 3.13 (1H, d, J = 12.8Hz), 3.26-3.28 (1H, m), 4.35-5.05 (1H, br), 7.05-7.18 (2H, m), 7.30-7.40(2H, m), 9.30-9.55 (1H, br), 9.75-10.02 (1H, br). Dihydro- chloride 17—O—

1H-NMR (DMSO-d6) δ ppm: 1.46 (3H, s), 1.84 (3H, s), 2.89 (1H, d, J =12.9 Hz), 3.47-3.88 (3H, m), 3.81-3.97 (2H, m), 4.01-4.15 (1H, m),4.34-4.46 (1H, m), 7.28 (1H, dd, J = 2.3, 5.8 Hz), 7.38-7.44 (1H, m),7.44-7.50 (1H, m), 7.50-7.54 (1H, m), 7.80-7.87 (2H, m), 7.59 (1H, d, J= 8.1 Hz), 9.84-10.04 (1H, br), 10.04-10.20 (1H, br). Hydro- chloride

TABLE 3 Relative configuration

Example R⁴ NMR Salt 18

1H-NMR (DMSO-d6) δ ppm (80° C.): 1.40 (3 H, s), 1.43-1.70 (5 H, m),1.72-1.92 (2 H, m), 1.95-2.23 (4 H, m), 3.39-3.52 (2 H, m), 3.55-4.02 (1H, br), 4.02-4.14 (1 H, m), 5.64-6.00 (1 H, br), 7.31-7.38 (1 H, m),7.38-7.47 (2 H, m), 7.50-7.57 (1H, m), 7.72-7.85 (3 H, m), 8.44-8.80 (1H, br), 9.04-9.40 (1 H, br). Dihydro- chloride 19

1H-NMR (DMSO-d6) δ ppm (80° C.): 1.31-1.51 (5H, m), 1.54 (3H, s),1.83-1.76 (2H, m), 1.87-2.12 (3H, m), 2.12-2.23 (1H, m), 3.22-3.44 (2H,m), 3.85-4.02 (2H, m), 5.00-5.90 (1H, br), 7.33 (1H, d, J = 6.6 Hz),7.36 (1H, d, J = 5.4 Hz), 7.70 (1H, d, J = 5.4 Hz), 7.77 (1H, s), 7.89(1H, d, J = 8.8 Hz), 8.25-8.74 (1H, br), 9.00-9.54 (1H, br). Dihydro-chloride 20

1H-NMR (DMSO-d6) δ ppm: 1.34 (3H, s), 1.39-1.55 (5H, m), 1.67-1.90 (3H,m), 1.90-2.15 (3H, m), 3.17-3.35 (2H, m), 3.75-4.02 (2H, m), 7.10-7.20(2H, m), 7.25-7.37 (2H, m), 7.37-7.90 (1H, br), 5.45-6.69 (1H, br),5.59-9.19 (1H, br). Dihydro- chloride

TABLE 4 Relative configuration

Exam- ple R⁴ NMR Salt 21

1H-NMR (DMSO-d6) δ ppm (80° C.): 1.43 (3H, s), 1.47 (3H, s), 1.61-1.65(1H, m), 1.72-1.90 (3H, m), 1.93-2.09 (2H, m), 2.12-2.29 (2H, m),3.59-3.80 (1H, m), 3.81-3.92 (1H, m), 3.98-4.11 (1H, m), 4.11-4.70 (2H,br), 7.22-7.45 (4H, m), 7.70-7.85 (3H, m), 9.15-9.49 (1H, br), 9.49-9.58(1H, br). Dihydro- chloride 22

1H-NMR (DMSO-d6) δ ppm (80° C.): 1.48 (3H, s), 1.49 (3H, s), 1.85-1.94(5H, m), 2.10-2.44 (3H, m), 3.89-3.90 (1H, m), 3.85-4.00 (1H, m),4.00-4.20 (1H, m), 4.80-4.96 (1H, m), 4.95-6.06 (1H, br), 7.36-7.55 (2H,m), 7.76 (1H, d, J = 5.4 Hz), 7.78 (1H, brs), 7.98 (1H, d, J = 6.8 Hz),9.40-9.65 (1H, br), 9.86-10.11 (1H, br). Dihydro- chloride 23

1H-NMR (DMSO-d6) δ ppm (80° C.): 1.44 (6H, m), 1.47-1.84 (1H, m),1.67-1.54 (3H, m), 1.85-2.13 (3H, m), 2.14-2.30 (1H, m), 3.60-3.80 (2H,m), 3.92-4.07 (1H, m), 5.80-5.70 (1H, br), 7.04 (1H, d, J = 6.9 Hz),7.25 (1H, d, J = 5.9 Hz), 9.40-9.75 (2H, br). Dihydro- chloride

TABLE 5 Relative configuration

Ex- am- ple R¹ R⁴ NMR Salt 24 —H

1H-NMR (DMSO) δ ppm: 1.29-1.67 (3H, m), 1.46 (3H, s), 1.57 (3H, s),1.89-1.91 (4H, m), 1.98-2.09 (1H, m), 3.07 (1H, d, J = 13.5 Hz), 3.51(1H, d, J = 13.5 Hz), 3.73-3.92 (1H, m), 4.11-4.30 (1H, m), 7.18 (1H, d,J = 2.2 Hz), 7.22-7.28 (1H, m), 7.36-7.43 (2H, m), 7.88-7.50 (3H, m),5.02-8.51 (1H, m), 9.52-9.91 (1H, br) Hydro- chloride 25 —CH₃

1H-NMR (CDCl3) δ ppm: 1.21-1.35 (1H, m), 1.40-1.53 (1H, m), 1.48 (3H,s), 1.55-1.77 (2H, m), 1.93 (3H, s), 1.98-2.05 (1H, m), 2.18-2.34 (1H,m), 2.37-2.58 (1H, m), 2.87-2.58 (1H, m), 2.82 (3H, d, J = 4.9 Hz), 3.26(1H, d, J = 13.4 Hz), 3.64-3.77 (1H, m), 3.91 (1H, d, J = 13.4 Hz),3.97-4.04 (1H, m), 7.07-7.09 (1H, m), 7.17-7.22 (1H, m), 7.30-7.35 (1H,m), 7.40-7.46 (1H, m), 7.68-7.53 (3H, m), 11.27 (1H, brs) Hydro-chloride 26 —H

1H-NMR (DMSO-d6) δ ppm: 1.2-1.5 (6H, m), 1.57 (3H, s), 1.6-1.95 (4H, m),1.95-2.15 (1H, m), 3.05 (1H, d, J = 13.3 Hz), 3.40 (1H, d, J = 13.4 Hz),3.75-3.9 (4H, m), 4.05-4.2 (1H, m), 4.93 (1H, br), 7.07 (1H, dd, J =2.5, 8.9 Hz), 7.1-7.2 (2H, m), 7.36 (1H, dd, J = 2.3, 9.1 Hz), 7.65 (1H,d, J = 9.0 Hz), 7.70 (1H, d, J = 9.1 Hz), 6.06-8.3 (1H, m), 9.76-10.05(1H, m). Dihydro- chloride 27 —H

1H-NMR (DMSO-d6) δ ppm: 0.9-1.1 (2H, m), 1.25-1.45 (1H, m), 1.45-1.7(7H, m), 1.7-2.1 (4H, m), 2.55 (1H, d, J = 12.7 Hz), 3.43 (1H, d, J =12.5 Hz), 3.55-3.7 (1H, m), 4.1-4.3 (1H, m), 6.02 (1H, d, J = 7.7 Hz),7.28 (1H, dd, J = 7.8, 7.6 Hz), 7.5-7.7 (2H, m), 7.74 (1H, d, J = 5.5Hz), 7.9-8.2 (1H, m), 9.55-9.85 (1H, m). Hydro- chloride 28 —H

1H-NMR (CDCl3) δ ppm: 1.18-1.28 (1H, m), 1.38-1.50 (2H, m), 1.55 (3H,s), 1.72-2.00 (2H, m), 1.90 (3H, s), 2.07-2.22 (1H, m), 2.39-2.52 (2H,m), 3.05 (1H, d, J = 12.8 Hz), 8.43 (1H, d, J = 1.25 Hz), 3.77-3.90 (1H,m), 3.91-4.01 (1H, m), 7.04 (1H, dd, J = 8.8, 2.2 Hz), 7.21-7.25 (2H,m), 7.43 (1H, d, J = 5.4 Hz), 7.75 (1H, d, J = 8.5 Hz), 8.55-8.97 (1H,br), 9.99-10.37 (1H, br) Hydro- chloride 29 —CH₃

1H-NMR (CDCl3) δ ppm: 1.17-1.34 (1H, m), 1.37-1.74 (2H, m), 1.47 (3H,s), 1.57-2.04 (1H, m), 1.90 (3H, s), 2.20-2.30 (1H, m), 2.39-2.54 (1H,m), 2.84-2.88 (2H, m), 2.75 (3H, d, J = 4.9 Hz), 3.12 (1H, d, J = 13.2Hz), 3.89-3.74 (1H, m), 3.85-3.93 (1H, m), 3.87 (1H, d, J = 13.2 Hz),7.01 (1H, dd, J = 5.6, 2.2 Hz), 7.21-7.32 (2H, m), 7.44 (1H, d, J = 5.4Hz), 7.75 (1H, d, J = 5.8 Hz), 11.20 (1H, brs) Hydro- chloride 30 —H

1H-NMR (CDCl3) δ ppm: 1.11-1.33 (1H, m), 1.35-1.54 (2H, m), 1.85 (3H,s), 1.72-2.00 (2H, m), 1.90 (3H, s), 2.07-2.29 (1H, m), 2.34-2.50 (2H,m), 3.03 (1H, d, J = 13.2 Hz), 3.42 (1H, d, J = 13.2 Hz), 3.76-4.02 (2H,m), 7.02 (1H, dd, J = 8.7, 2.2 Hz), 7.17-7.31 (3H, m), 7.70 (1H, d, J =5.7 Hz), 8.64-9.00 (1H, br), 10.08-10.37 (1H, br) Hydro- chloride 31—CH₃

1H-NMR (CDCl3) δ ppm: 1.20-1.35 (1H, m), 1.38-1.74 (3H, m), 1.45 (3H,s), 1.90 (3H, s), 1.97-2.11 (1H, m), 2.20-2.30 (1H, m), 2.41-2.56 (1H,m), 2.85-2.89 (1H, m), 2.81 (3H, d, J = 4.5 Hz), 3.16 (1H, d, J = 13.3Hz), 3.61-3.74 (1H, m), 3.88 (1H, d, J = 13.3 Hz), 3.89-3.99 (1H, m),6.99 (1H, dd, J = 5.7, 2.1 Hz), 7.20-7.31 (3H, m), 7.70 (1H, d, J = 8.7Hz), 11.04-11.44 (1H, br) Hydro- chloride 32 —H

1H-NMR (DMSO-d6) δ ppm: 0.9-1.2 (2H, m), 1.25-1.45 (1H, m), 1.53 (5H,s), 1.8-1.7 (1H, m), 1.7-1.9 (2H, m), 1.9-2.15 (2H, m), 2.92 (1H, d, J =2.8 Hz), 3.46 (1H, d, J = 12.7 Hz), 3.75-4.0 (2H, m), 7.02 (1H, d, J =7.5 Hz), 7.34 (1H, dd, J = 7.7, 7.7 Hz), 7.48 (1H, d, J = 5.4 Hz), 7.51(1H, d, J = 7.8 Hz), 7.78 (1H, d, J = 5.4 Hz), 8.17 (1H, br), 9.75 (1H,br). Hydro- chloride 33 —H

1H-NMR (DMSO-d6) δ ppm: 0.95-1.15 (2H, m), 1.3-1.45 (1H, m), 1.51 (3H,s), 1.53 (3H, s), 1.6-2.1 (8H, m), 3.04 (1H, d, J = 12.9 Hz), 3.2-3.45(1H, m), 3.75-3.95 (1H, m), 3.95-4.15 (1H, m), 8.6-8.8 (1H, m), 7.1-7.3(3H, m), 7.94 (1H, d, J = 2.1 Hz), 8.07 (1H, br), 9.77 (1H, br). Hydro-chloride

TABLE 6 Relative configuration

Ex- am- ple R¹ R⁴ NMR Salt 34 —H

1H-NMR (CDCl3) δ ppm: 1.15 (18H, d, J = 7.5 Hz), 1.20 (3H, s), 1.25-1.45(8H, m), 1.45-1.8 (8H, m), 1.8-2.0 (1H, m), 2.83 (1H, d, J = 11.5 Hz),3.11 (1H, d, J = 11.5 Hz), 3.6-3.65 (1H, m), 3.67-3.8 (1H, m), 6.50 (1H,d, J = 7.2 Hz), 8.64 (1H, d, J = 2.7 Hz), 7.00 (1H, dd, J = 7.9, 7.9Hz), 7.11 (1H, d, J = 8.3 Hz), 7.16 (1H, d, J = 3.2 Hz). — 35 —H

1H-NMR (CDCl3) δ ppm: 1.13 (18H, d, J = 7.5 Hz), 1.21 (3H, s), 1.25-1,3(5H, m), 1.35-1.45 (2H, m), 1.53 (1H, br), 1.6-1.8 (7H, m), 2.80 (1H, d,J = 11.7 Hz), 2.93 (1H, d, J = 11.5 Hz), 3.45-3.55 (1H, m), 3.55-3.65(1H, m), 5.48 (1H, d, J = 2.6 Hz), 6.85 (1H, dd, J = 2.4, 9.0 Hz), 7.02(1H, d, J = 2.4 Hz), 7.16 (1H, d, J = 3.2 Hz), 7.36 (1H, d, J = 9.1 Hz).— 36 —H

1H-NMR (CDCl3) δ ppm: 1.1-1.2 (1H, m), 1.21 (3H, s), 1.25-1.3 (4H, m),1.3-1.85 (11H, m), 2.79 (1H, d, J = 11.6 Hz), 2.91 (1H, d, J = 11.5 Hz),3.45-3.65 (2H, m), 5.45-6.5 (1H, m), 6.82 (1H, dd, J = 2.0, 8.8 Hz),6.93 (1H, s), 7.08 (1H, d, J = 3.2 Hz), 7.45 (1H, d, J = 8.6 Hz). —

TABLE 7 Relative configuration

Example R¹ R⁴ NMR Salt 37 —H

1H-NMR (CDCl3) δ ppm: 0.95-1.15 (3H, m), 1.21 (3H, s), 1.25-1.45 (6H,m), 1.45-1.8 (2H, m), 1.6-1.95 (1H, m), 2.83 (1H, d, J = 11.5 Hz), 3.11(1H, d, J = 11.5 Hz), 3.6-3.7 (1H, m), 3.75-3.85 (1H, m), 6.50 (1H, dd,J = 0.9, 7.4 Hz), 6.55-6.6 (1H, m), 7.00 (1H, d, J = 8.1 Hz), 7.07 (1H,dd, J = 7.7, 7.7 Hz), 7.14 (1H, dd, J = 2.8, 2.8 Hz), 8.18 (1H, br). —38 —CH₃

1H-NMR (CDCl3) δ ppm: 1.0-1.15 (5H, m), 1.19 (3H, s), 1.2-1.5 (3H, m),1.6-1.7 (1H, m), 2.8-2.3 (5H, m), 2.76 (1H, d, J = 11.5 Hz), 3.05-3.15(1H, m), 3.38 (1H, d, J = 11.4 Hz), 3.8-3.9 (1H, m), 8.49 (1H, d, J =7.4 Hz), 6.55-6.6 (1H, m), 6.99 (1H, d, J = 7.4 Hz), 7.07 (1H, dd, J =7.8, 7.8 Hz), 7.13 (1H, dd, J = 2.8, 2.8 Hz), 8.11 (1H, br). — 39 —H

1H-NMR (CDCl3) δ ppm: 1.0-1.85 (15H, m), 2.82 (1H, d, J = 11.5 Hz), 2.88(1H, d, J = 11.5 Hz), 3.45-3.55 (1H, m), 3.55-3.65 (1H, m), 8.4-6.45(1H, m), 6.95 (1H, dd, J = 2.3, 8.8 Hz), 7.04 (1H, d, J = 2.2 Hz), 7.13(1H, dd, J = 2.8, 2.8 Hz), 7.25-7.3 (1H, m), 7.98 (1H, br). — 40 —CH₃

1H-NMR (CDCl3) δ ppm: 1.06 (3H, s), 1.1-1.55 (8H, m), 1.6-1.75 (1H, m),1.95-2.15 (2H, m), 2.16 (3H, s), 2.80 (1H, d, J = 11.4 Hz), 2.95-3.0(1H, m), 3.10 (1H, d, J = 11.4 Hz), 3.55-3.7 (1H, m), 6.35-5.45 (1H, m),6.94 (1H, dd, J = 2.3, 5.6 Hz), 7.03 (1H, d, J = 2.0 Hz), 7.12 (1H, dd,J = 2.8, 2.8 Hz), 7.2-7.3 (1H, m), 7.94 (1H, br). — 41 —H

1H-NMR (DMSO-d6) δ ppm: 1.0-1.4 (9H, m), 1.4-1.9 (5H, m), 2.62 (1H, d, J= 11.9 Hz), 2.95 (1H, d, J = 12.0 Hz), 3.0-4.5 (4H, m), 6.25 (1H, dd, J= 2.4, 2.4 Hz), 6.47 (1H, s), 6.7-8.8 (2H, m), 7.10 (1H, dd, J = 2.7,2.7 Hz), 7.34 (1H, d, J = 9.3 Hz), 10.65 (1H, s). Hemi- fumarate 42 —CH₃

1H-NMR (DMSO-d6) δ ppm: 0.95-1.5 (1H, m), 1.55-1.7 (1H, m), 1.55-2.1(2H, m), 2.16 (3H, s), 2.65-4.2 (6H, m), 6.2-6.25 (1H, m), 6.80 (2H, s),5.7-6.6 (2H, s), 7.09 (1H, dd, J = 2.4, 3.0 Hz), 7.33 (1H, d, J = 6.6Hz), 10.80 (1H, s). Fumarate 43 —H

1H-NMR (DMSO-d6) δ ppm: 0.95-1.4 (9H, m), 1.45-1.9 (5H, m), 2.88 (2H,dd, J = 12.3, 15.1 Hz), 3.5-3.8 (1H, m), 3.6-3.75 (4H, m), 6.24 (1H, dd,J = 0.6, 3.0 Hz), 6.47 (1H, s), 6.85-7.0 (2H, m), 7.18 (1H, d, J = 3.0Hz), 7.27 (1H, d, J = 9.5 Hz). Hemi- fumarate 44 —H

1H-NMR (DMSO-d6) δ ppm: 1.1-1.4 (9H, m), 1.4-1.9 (6H, m), 2.65 (1H, d, J= 12.1 Hz), 3.03 (1H, d, J = 12.1 Hz), 3.5-3.6 (1H, m), 3.69 (3H, s),3.75-3.85 (1H, m), 6.24 (1H, d, J = 3.1 Hz), 6.49 (2H, s), 6.7-6.85 (2H,m), 7.07 (1H, d, J = 3.1 H), 7.34 (1H, d, J = 5.6 Hz). Fumarate 45 —H

1H-NMR (DMSO-d6) δ ppm: 1.0-1.3 (2H, m), 1.3-1.45 (7H, m), 1.5-1.95 (5H,m), 2.9-3.1 (2H, m), 3.71 (1H, br), 3.8-3.95 (1H, m), 3.98 (3H, s), 6.54(3H, s), 7.04 (1H, s), 7.27 (1H, dd, J = 1.9, 9.2 Hz), 7.51 (1H, d, J =9.1 Hz), 7.83 (1H, s), 10.8 (4H, br). 3/2 Fumarate 46 —H

1H-NMR (DMSO-d6) δ ppm: 1.1-1.35 (2H, m), 1.35-1.45 (4H, m), 1.50 (3H,s), 1.6-1.9 (4H, m), 1.9-2.1 (1H, m), 2.92 (1H, d, J = 13.2 Hz), 3.11(1H, d, J = 13.2 Hz), 3.5-4.05 (3H, m), 5.91 (2H, d, J = 1.0 Hz), 6.32(1H, dd, J = 2.4, 8.5 Hz), 6.71 (1H, d, J = 2.3 Hz), 6.76 (1H, d, J =8.4 Hz), 8.06 (1H, br), 9.83 (1H, br). Dihydro- chloride

TABLE 8 Relative configuration

Ex- am- ple R¹ R⁵ R⁶ R⁷ R⁸ R⁹ NMR Salt 47 —H —H —H —F —H —H 1H-NMR(DMSO-d6) δ ppm: 1.1-1.35 (2H, m), 1.35-1.5 (4H, m), 1.53 (3H, s),Dihydro- 1.6-1.95 (4H, m), 1.95-2.15 (1H, m), 2.94 (1H, d, J = 13.3 Hz),3.24 (1H, d, chloride J = 13.2 Hz), 3.65-3.85 (1H, m), 3.85-4.0 (1H, m),5.30 (1H, br), 6.9-7.0 (2H, m), 7.0-7.1 (2H, m), 8.0-8.35 (1H, m), 10.03(1H, d, J = 10.5 Hz). 48 —H —H —H —F —F —H 1H-NMR (DMSO-d6) δ ppm:1.2-1.35 (6H, m), 1.52 (3H, s), 1.6-1.95 (4H, m), Hydro- 1.96-2.15 (1H,m), 2.93 (1H, d, J = 13.5 Hz), 3.36 (1H, d, J = 13.5 Hz), 3.65-3.8chloride (1H, m), 3.9-4.1 (1H, m), 5.5-6.5 (1H, m), 6.9-7.1 (1H, m),7.25 (1H, dd, J = 9.5, 19.7 Hz), 8.0-8.4 (1H, m), 10.02 (1H, d, J = 11.3Hz). 49 —H —H —F —H —F —H 1H-NMR (DMSO-d6) δ ppm: 1.25-1.6 (9H, m),1.8-2.05 (5H, m), 2.95 (1H, d, Hydro- J = 14.5 Hz), 3.56 (1H, d, J =13.9 Hz), 3.6-3.75 (1H, m), 4.0-4.15 (1H, m), chloride 6.35-6.55 (1H,m), 8.5-8.75 (2H, m), 5.05-8.4 (1H, m), 9.65-10.2 (1H, m). 50 —H —H —F—OCH₃ —F —H 1H-NMR (DMSO-d6) δ ppm: 1.21-1.45 (6H, m), 1.80 (3H, s),1.8-1.9 (4H, m), Hydro- 1.9-2.05 (1H, m), 2.90 (1H, d, J = 13.7 Hz),3.42 (1H, d, J = 13.7 Hz), 3.8-3.75 chloride (1H, m), 3.78 (3H, s),3.9-4.05 (1H, m), 6.65-6.8 (2H, m), 8.17 (1H, br), 9.86 (1H, br). 51—CH₃ —H —F —OCH₃ —F —H 1H-NMR (DMSO-d6) δ ppm: 0.96 (3H, s), 1.05-1.2(4H, m), 1.2-1.5 (4H, m), 3/2 1.55-1.75 (1H, m), 1.85-2.1 (2H, m), 2.16(3H, s), 2.75-2.9 (2H, m), 3.12 Fumarate (1H, d, J = 12.4 Hz), 3.65-3.85(4H, m), 8.55-8.85 (5H, m). 52 —H —H —Cl —H —H —H 1H-NMR (DMSO-d6) δppm: 1.2-1.45 (6H, m), 1.51 (3H, s), 1.6-2.05 (5H, m), Hydro- 2.94 (1H,d, J = 13.7 Hz), 3.48 (1H, d, J = 14.0 Hz), 3.65-3.8 (1H, m), 4.0-4.15chloride (1H, m), 6.77 (1H, dd, J = 1.5, 7.8 Hz), 6.90 (1H, dd, J = 2.3,8.4 Hz), 6.95-7.0 (1H, m), 7.21 (1H, dd, J = 8.1, 8.1 Hz), 8.14 (1H,br), 9.55-10.0 (1H, m). 53 —CH₃ —H —Cl —H —H —H 1H-NMR (DMSO-d6) δ ppm:0.97 (3H, s), 1.05-1.2 (4H, m), 1.2-1.8 (4H, m), Fumarate 1.6-1.75 (1H,m), 1.9-2.1 (2H, m), 2.15 (3H, s), 2.85-5.05 (6H, m), 6.61 (2H, s), 6.86(1H, dd, J = 1.2, 7.8 Hz), 6.75-6.9 (2H, m), 7.15 (1H, dd, J = 8.1, 8.1Hz). 54 —H —H —H —Cl —H —H 1H-NMR (DMSO-d6) δ ppm: 1.15-1.45 (8H, m),1.62 (3H, s), 1.6-2.1 (5H, m), Hydro- 2.93 (1H, d, J = 13.5 Hz), 3.39(1H, d, J = 13.9 Hz), 3.65-3.8 (1H, m), 3.9-4.1 chloride (1H, m),5.9-7.0 (2H, m), 7.15-7.3 (2H, m), 7.95-8.4 (1H, m), 9.65-10.1 (1H, m).55 —CH₃ —H —H —Cl —H —H 1H-NMR (DMSO-d6) δ ppm: 0.99 (3H, s), 1.06-1.5(8H, m), 1.55-1.75 (1H, Fumarate m), 1.54-2.1 (2H, m), 2.17 (3H, s),2.8-2.95 (2H, m), 3.12 (1H, d, J = 12.3 Hz), 3.7-3.85 (1H, m), 6.61 (2H,s), 6.6-6.9 (2H, m), 7.1-7.2 (2H, m). 56 —H —H —Cl —Cl —H —H 1H-NMR(DMSO-d6) δ ppm: 1.21-1.62 (2H, m), 1.38 (3H, s), 1.53 (3H, s), Hydro-1.67-2.09 (6H, m), 2.95 (1H, d, J = 13.6 Hz), 3.48 (1H, d, J = 13.6 Hz),3.70-3.74 chloride (1H, m), 4.04-4.10 (1H, m), 6.95 (1H, dd, J = 8.7,2.6 Hz), 7.17 (1H, d, J = 2.8 Hz), 7.40 (1H, d, J = 6.7 Hz), 8.03-8.52(1H, br), 9.77-10.21 (1H, br) 57 —CH₃ —H —Cl —Cl —H —H 1H-NMR (CDCl3) δppm: 1.23-1.72 (4H, m), 1.42 (3H, s), 1.89 (3H, s), Hydro- 2.01-2.11(1H, m), 2.20-2.29 (1H, m), 2.37-2.65 (1H, m), 2.68-2.83 (1H, m),chloride 2.79 (3H, d, J =4.8 Hz), 3.09 (1H, d, J = 13.5 Hz), 3.54-3.65(1H, m), 3.75-3.83 (1H, m), 3.76 (1H,d, J = 13.5 Hz), 8.88 (1H, dd, J =9.0, 2.9 Hz), 6.92 (1H, d, J = 2.9 Hz), 7.30 (1H, d, J = 9.0 Hz), 11.48(1H, brs) 58 —H —H —Cl —F —H —H 1H-NMR (DMSO) δ ppm: 1.24-1.57 (3H, m),1.37 (3H, s), 1.52 (3H, s), Hydro- 1.64-1.81 (4H, m), 1.87-2.01 (1H, m),2.92 (1H, d, J = 13.1 Hz), 3.45 (1H, d, J = chloride 13.1 Hz), 3.65-3.79(1H, m), 3.90-4.06 (1H, m), 6.89-6.94 (1H, m), 7.08-7.11 (1H, m),7.20-7.27 (1H, m), 7.90-8.21 (1H, br), 9.55-9.81 (1H, br)

TABLE 9 Absolute configuration

Ex- am- ple R¹ R⁴ NMR Salt 59 —H

1H-NMR (CDCl3) δ ppm: 1.15-1.35 (5H, m), 1.35-1.86 (7H, m), 2.82 (1H, d,J = 11.7 Hz), 3.05 (1H, d, J = 11.8 Hz), 3.45-3.55 (1H, m), 3.7-3.8 (1H,m), 3.88 (3H, s), 8.97 (1H, d, J = 2.4 Hz), 7.0-7.1 (2H, m), 7.22-7.29(1H, m), 7.55 (1H, d, J = 8.8 Hz), 7.61 (1H, d, J = 9.0 Hz). — 60 —H

1H-NMR (CDCl3) δ ppm: 1.15-1.3 (8H, m), 1.3-1.5 (6H, m), 1.85-1.86 (4H,m), 2.82 (1H, d, J = 11.7 Hz), 3.04 (1H, d, J = 11.7 Hz), 3.45-3.85 (1H,m), 3.7-3.78 (1H, m), 4.11 (2H, q, J = 7.0 Hz), 8.96 (1H, d, J = 2.4Hz), 7.03 (1H, d, J = 2.4 Hz), 7.08 (1H, dd, J = 2.5, 5.8 Hz), 7.2-7.3(1H, m), 7.55 (1H, d, J = 8.9 Hz), 7.59 (1H, d, J = 9.0 Hz). — 61 —H

1H-NMR (DMSO-d6) δ ppm: 1.26-1.5 (8H, m), 1.56 (3H, s), 1.85-2.1 (5H,m), 3.06 (1H, d, J = 13.4 Hz), 3.46 (1H, d, J = 13.4 Hz), 3.8-3.9 (1H,m), 4.1-4.2 (1H, m), 4.42 (1H, br), 7.24 (1H, d, J = 2.3 Hz), 7.31 (1H,ddd, J = 4.5, 12.6, 12.5 Hz), 7.47 (1H, dd, J = 2.3, 9.2 Hz), 7.54 (1H,dd, J = 2.8, 10.2 Hz), 7.75-7.8 (2H, m), 8.1-8.25 (1H, m), 9.75-9.95(1H, m). Dihydro- chloride 62 —H

1H-NMR (DMSO-d6) δ ppm: 0.9-1.1 (2H, m), 1.3-1.4 (1H, m), 1.5-1.86 (7H,m), 1.65-1.85 (2H, m), 1.9-2.1 (2H, m), 2.81 (1H, d, J = 1.25 Hz),3.4-3.5 (2H, m), 4.2-4.35 (1H, m), 7.13 (1H, d, J = 7.0 Hz), 7.43 (1H,dd, J = 7.8, 7.5 Hz), 7.5-7.8 (2H, m), 7.65 (1H, d, J = 8.2 Hz),7.55-7.95 (1H, m), 7.95-8.15 (1H, m), 5.2-8.3 (1H, m), 9.65-9.85 (1H,m). Hydro- chloride 63 —H

1H-NMR (DMSO-d6) δ ppm: 0.9-1.15 (2H, m), 1.3-1.4 (1H, m), 1.5-1.7 (7H,m), 1.7-1.85 (2H, m), 1.9-2.1 (2H, m), 2.77 (1H, d, J = 12.5 Hz),3.3-3.45 (1H, m), 3.52 (1H, d, J = 12.5 Hz), 4.2-4.3 (1H, m), 7.05-7.15(1H, m), 7.25 (1H, dd, J = 8.2, 10.5 Hz), 7.6-7.7 (2H, m), 8.0-8.15 (2H,m), 8.3-8.4 (1H, m), 9.7-9.95 (1H, m). Hydro- chloride

TABLE 10 Absolute configuration

Ex- am- ple R¹ R⁴ NMR Salt 64 —H

1H-NMR (DMSO-d6) δ ppm: 0.9-1.1 (2H, m), 1.3-1.4 (1H, m), 1.5-1.7 (7H,m), 1.7-1.9 (2H, m), 1.95-2.15 (2H, m), 2.89 (1H, d, J = 12.7 Hz),3.0-4.2 (4H, m), 4.3-4.4 (1H, m), 7.35-7.5 (1H, m), 7.8-8.05 (3H, m),8.05-8.3 (1H, m), 9.1-9.4 (2H, m), 10.0-10.25 (1H, m). Trihydro-chloride 65 —H

1H-NMR (CDCl3) δ ppm: 0.9-1.05 (3H, m), 1.24 (3H, s), 1.36-1.45 (5H, m),1.55-1.8 (3H, m), 1.9-2.05 (1H, m), 2.71 (1H, d, J = 11.3 Hz), 3.25 (1H,d, J = 11.3 Hz), 3.85-3.75 (1H, m), 3.75-3.85 (1H, m), 8.76 (1H, d, J =5.0 Hz), 7.45-7.8 (1H, m), 7.5-7.7 (1H, m), 8.0-8.1 (2H, m), 8.88 (1H,d, J = 5.0 Hz). — 66 —H

1H-NMR (DMSO-d6) δ ppm: 1.36-1.5 (5H, m), 1.82 (3H, s), 1.7-2.0 (3H, m),2.6-2.15 (2H, m), 2.7-4.3 (4H, m), 4.25-4.4 (1H, m), 7.67 (1H, d, J =2.5 Hz), 7.80 (1H, d, J = 5.2, 5.6 Hz), 5.04 (1H, dd, J = 2.7, 9.6 Hz),8.24 (1H, d, J = 9.5 Hz), 8.5-8.8 (1H, m), 8.79 (1H, d, J = 8.4 Hz),8.98 (1H, dd, J = 1.5, 6.2 Hz), 10.22 (1H, d, J = 10.1 Hz). Dihydro-chloride 67 —H

1H-NMR (DMSO-d6) δ ppm: 1.41 (3H, s), 1.45-1.8 (3H, m), 1.82 (3H, s),1.7-1.85 (2H, m), 1.55-2.0 (1H, m), 2.05-2.25 (2H, m), 3.27 (1H, d, J =14.5 Hz), 3.37 (1H, br), 3.75-3.85 (1H, m), 4.09 (1H, d, J = 14.4 Hz),4.4-4.5 (1H, m), 7.80 (1H, d, J = 2.1 Hz), 7.85 (1H, dd, J = 2.4, 9.5Hz), 7.93 (1H, d, J = 8.8 Hz), 8.25-5.35 (2H, m), 8.6-8.75 (1H, m), 9.36(1H, s), 10.2-10.4 (1H, m). Dihydro- chloride

TABLE 11 Absolute configuration

Example R¹ R⁴ NMR Salt 68 —H

1H-NMR (CDCl3) δ ppm: 0.9-1.1 (2H, m), 1.22 (3H, s), 1.3-1.45 (6H, m),1.45-1.8 (3H, m), 1.8-2.0 (1H, m), 2.65 (1H, d, J = 11.3 Hz), 3.19 (1H,d, J = 11.3 Hz), 3.45-3.85 (1H, m), 3.65-3.75 (1H, m), 6.79 (1H, d, J =7.6 Hz), 7.15-7.3 (1H, m), 7.38 (1H, d, J = 5.8 Hz), 7.44 (1H, d, J =5.5 Hz), 7.51 (1H, d, J = 8.0 Hz). — 69 —H

1H-NMR (DMDO-d6) δ ppm: 1.1-1.35 (2H, m), 1.35-1.5 (4H, m), 1.65 (3H,s), 1.8-2.15 (5H, m), 3.08 (1H, d, J = 13.2 Hz), 3.35 (1H, d, J = 13.2Hz), 3.71 (1H, br), 3.75-3.9 (1H, m), 3.95-4.15 (1H, m), 7.18 (1H, dd, J= 2.1, 9.0 Hz), 7.29 (1H, d, J = 5.4 Hz), 7.35 (1H, d, J = 2.0 Hz), 7.68(1H, d, J = 5.4 Hz), 7.82 (1H, d, J = 8.9 Hz), 6.05-8.25 (1H, m),9.75-10.0 (1H, m). Dihydro- chloride 70 —CH₃

1H-NMR (DMDO-d6) δ ppm: 0.95-1.5 (11H, m), 1.55-1.75 (1H, m), 1.85-2.1(2H, m), 2.19 (3H, s), 2.85-5.05 (5H, m), 6.61 (2H, s), 7.10 (1H, dd, J= 2.4, 9.0 Hz), 7.24 (1H, d, J = 2.3 Hz), 7.27 (1H, dd, J = 0.5, 5.4Hz), 7.62 (1H, d, J = 5.4 Hz), 7.75 (1H, d, J = 8.9 Hz). Fumarate 71 —H

1H-NMR (DMDO-d6) δ ppm: 1.2-1.5 (6H, m), 1.54 (3H, s), 1.8-2.1 (5H, m),3.03 (1H, d, J = 13.4 Hz), 3.43 (1H, d, J = 13.5 Hz), 3.7-3.9 (1H, m),4.0-4.2 (1H, m), 7.14 (1H, dd, J = 2.2, 8.9 Hz), 7.27 (1H, d, J = 5.4Hz), 7.4-7.55 (2H, m), 7.71 (1H, d, J = 5.8 Hz), 8.14 (1H, br), 9.84 1H,br). Hydro- chloride 72 —H

1H-NMR (DMDO-d6) δ ppm: 0.95-1.2 (2H, m), 1.3-1.45 (1H, m), 1.45-1.7(7H, m), 1.7-1.9 (2H, m), 1.9-2.2 (2H, m), 2.91 (1H, d, J = 12.8 Hz),3.48 (1H, d, J = 12.9 Hz), 3.75-4.0 (2H, m), 7.01 (1H, d, J = 7.5 Hz),7.34 (1H, dd, J = 7.7, 7.7 Hz), 7.48 (1H, d, J = 5.4 Hz), 7.61 (1H, d, J= 7.7 Hz), 7.76 (1H, d, J = 5.4 Hz), 8.24 (1H, br), 9.94 (1H, br).Hydro- chloride

TABLE 12 Absolute configuration

Example R¹ R⁴ NMR Salt 73 —H

1H-NMR (DMDO-d6) δ ppm: 0.95-1.15 (2H, m), 1.3-1.45 (1H, m), 1.51 (3H,s), 1.53 (3H, s), 1.65-2.05 (5H, m), 3.04 (1H, d, J = 1.29 Hz), 3.2-.34(1H, m), 3.75-3.9 (1H, m), 4.0-4.15 (1H, m), 6.71 (1H, dd, J = 3.0, 5.5Hz), 7.15-7.25 (3H, m), 7.94 (1H, d, J = 2.2 Hz), 8.08 (1H, br), 9.80(1H, br). Hydro- chloride 74 —H

1H-NMR (DMDO-d6) δ ppm: 1.1-1.35 (2H, m), 1.35-1.5 (4H, m), 1.54 (3H,s), 1.6-1.86 (4H, m), 1.35-2.1 (1H, m), 3.03 (1H, d, J = 13.1 Hz), 3.21(1H, d, J = 13.1 Hz), 3.75-3.9 (1H, m), 3.9-4.0 (1H, m), 4.53 (1H, br),5.5-5.85 (1H, m), 7.03 (1H, dd, J = 2.5, 9.0 Hz), 7.18 (1H, d, J = 2.4Hz), 7.46 (1H, d, J = 9.0 Hz), 7.90 (1H, d, J = 2.2 Hz), 8.11 (1H, br),9.91 (1H, br). Dihydro- chloride 75 —H

1H-NMR (DMDO-d6) δ ppm: 1.15-1.5 (8H, m), 1.65 (3H, s), 1.6-1.95 (4H,m), 1.95-2.15 (1H, m), 3.01 (1H, d, J = 13.4 Hz), 3.36 (1H, d, J = 13.1Hz), 3.7-3.85 (1H, m), 3.95-4.05 (1H, m), 4.50 (1H, br), 6.80 (1H, d, J= 2.1 Hz), 6.96 (1H, dd, J = 1.9, 8.7 Hz), 7.13 (1H, s), 7.47 (1H, d, J= 6.6 Hz), 7.79 (1H, d, J = 0.7H), 8.20 (1H, br), 9.85-10.2 (1H, m).Dihydro- chloride 76 —H

1H-NMR (DMDO-d6) δ ppm: 1.1-1.3 (2H, m), 1.35-1.45 (1H, m), 1.50 (3H,s), 1.54 (3H, s), 1.6-1.9 (3H, m), 1.9-2.1 (2H, m), 3.2-3.4 (2H, m),3.9-4.0 (1H, m), 4.15-4.25 (1H, m), 6.50 (1H, d, J = 7.2 Hz), 6.93 (1H,d, J = 2.2 Hz), 7.12 (1H, dd, J = 7.7, 7.7 Hz), 7.21 (1H, dd, J = 0.8,7.7 Hz), 7.97 (1H, d, J = 2.2 Hz), 8.1-8.35 (1H, m), 9.7-9.9 (1H, m).Hydro- chloride 77 —H

1H-NMR (CDCl3) δ ppm: 1.0-1.45 (11H, m), 1.6-1.8 (3H, m), 1.6-1.95 (1H,m), 2.70 (1H, d, J = 11.3 Hz), 3.04 (1H, d, J = 11.3 Hz), 3.50 (1H, ddd,J = 3.8, 3.8, 12.1 Hz), 3.55-3.85 (1H, m), 8.47 (1H, dd, J = 3.4, 8.6Hz), 6.84 (1H, dd, J = 2.5, 2.5 Hz), 6.89 (1H, dd, J = 8.8, 10.4 Hz),7.60 (1H, d, J = 2.2 Hz). — 78 —H

1H-NMR (CDCl3) δ ppm: 1.0-1.15 (2H, m), 1.20 (3H, s), 1.25-1.45 (5H, m),1.6-1.8 (3H, m), 1.8-1.95 (1H, m), 2.79 (1H, d, J = 11.5 Hz), 3.05 (1H,d, J = 11.4 Hz), 3.55-3.64 (2H, m), 6.53 (1H, d, J = 8.4 Hz), 6.84 (1H,d, J = 2.2 Hz), 7.14 (1H, d, J = 8.4 Hz), 7.51 (1H, d, J = 2.2 Hz). — 79—H

1H-NMR (DMDO-d6) δ ppm: 0.95-1.1 (2H, m), 1.3-1.4 (1H, m), 1.51 (3H, s),1.52 (3H, s), 1.5-1.7 (1H, m), 1.7-1.95 (3H, m), 1.95-2.05 (1H, m), 2.39(3H, s), 2.95 (1H, d, J = 12.8 Hz), 3.28 (1H, d, J = 12.9 Hz), 3.7-3.8(1H, m), 4.0-4.15 (1H, m), 8.61 (1H, d, J = 7.9 Hz), 6.99 (1H, d, J =8.0 Hz), 7.20 (1H, d, J = 2.2 Hz), 7.95 (1H, d, J = 2.2 Hz), 7.95-5.16(1H, m), 9.7-9.9 (1H, m). Hydro- chloride 80 —H

1H-NMR (DMDO-d6) δ ppm: 0.95-1.1 (2H, m), 1.3-1.4 (1H, m), 1.52 (8H, s),1.55-1.65 (1H, m), 1.55-1.95 (3H, m), 1.95-2.1 (1H, m), 2.85 (1H, d, J =12.7 Hz), 3.27 (1H, d, J = 12.8 Hz), 3.6-3.7 (1H, m), 3.87 (3H s),4.0-4.15 (1H, m), 6.51 (1H, d, J = 8.4 Hz), 8.79 (1H, d, J = 8.4 Hz),7.21 (1H, d, J = 2.2 Hz), 7.95 (1H, d, J = 2.2 Hz), 7.95-8.15 (1H, m),9.75-10.0 (1H, m). Hydro- chloride 81 —H

1H-NMR (DMDO-d6) δ ppm: 1.05-1.25 (2H, m), 1.35-1.45 (1H, m), 1.50 (3H,s), 1.53 (3H, s), 1.6-1.9 (3H, m), 1.9-2.1 (2H, m), 3.17 (1H, d, J =13.0 Hz), 3.29 (1H, d, J = 13.2 Hz), 3.9-4.0 (1H, m), 4.0-4.1 (1H, m),6.80 (1H, dd, J = 4.4, 8.7 Hz), 6.98 (1H, dd, J = 8.9, 5.9 Hz), 7.06(1H, d, J = 2.2 Hz), 5.06 (1H, d, J = 2.2 Hz), 8.1-8.3 (1H, m), 9.7-9.9(1H, m). Hydro- chloride

TABLE 13 Absolute configuration

Ex- am- ple R¹ R⁴ NMR Salt 82 —H

1H-NMR (CDCl3) δ ppm: 1.1-1.2 (20H, m), 1.20 (3H, s), 1.3-1.45 (6H, m),1.55-1.8 (6H, m), 1.8-2.0 (1H, m), 2.53 (1H, d, J = 11.5 Hz), 3.11 (1H,d, J = 11.5 Hz), 3.6-3.7 (1H, m), 3.7-3.8 (1H, m), 5.50 (1H, d, J = 7.4Hz), 5.64 (1H, d, J = 3.1 Hz), 7.00 (1H, dd, J = 7.9, 7.9 Hz), 7.11 (1H,d, J = 8.3 Hz), 7.16 (1H, d, J = 3.2 Hz). — 83 —H

1H-NMR (CDCl3) δ ppm: 1.13 (18H, d, J = 7.5 Hz), 1.21 (3H, s), 1.25 (3H,s), 1.3-1.6 (5H, m), 1.85-1.8 (7H, m), 2.80 (1H, d, J = 11.6 Hz), 2.93(1H, d, J = 11.8 Hz), 3.45-3.55 (1H, m), 3.55-3.85 (1H, m), 6.48 (1H, d,J = 3.1 Hz), 6.85 (1H, dd, J = 2.4, 9.0 Hz), 7.02 (1H, d, J = 2.4 Hz),7.18 (1H, d, J = 3.1 Hz), 7.35 (1H, d, J = 9.0 Hz). — 84 —H

1H-NMR (CDCl3) δ ppm: 1.1-1.2 (18H, m), 1.21 (3H, s), 1.20 (3H, s),1.3-1.5 (5H, m), 1.55-1.8 (7H, m), 2.79 (1H, d, J = 11.6 Hz), 2.91 (1H,d, J = 11.6 Hz), 3.45-3.6 (2H, m), 6.46 (1H, d, J = 3.2 Hz), 5.82 (1H,dd, J = 2.0, 8.6 Hz), 5.93 (1H, s), 7.08 (1H, d, J = 3.2 Hz), 7.45 (1H,d, J = 8.8 Hz). —

TABLE 14 Absolute configuration

Example R¹ R⁴ NMR Salt 85 —H

1H-NMR (CDCl3) δ ppm: 0.9-1.15 (2H, m), 1.21 (3H, s), 1.25-1.45 (5H, m),1.5-1.8 (4H, m), 1.8-2.0 (1H, m), 2.83 (1H, d, J = 11.5 Hz), 3.11 (1H,d, J = 11.5 Hz), 3.6-3.75 (1H, m), 3.75-3.85 (1H, m), 6.50 (1H, dd, J =0.9, 7.4 Hz), 6.55-6.6 (1H, m), 5.95-7.05 (1H, m), 7.07 (1H, dd, J =7.7, 7.7 Hz), 7.14 (1H, dd, J = 2.8, 2.5 Hz), 8.15 (1H, br). — 86 —H

1H-NMR (CDCl3) δ ppm: 1.0-1.25 (2H, m), 1.35 (7H, bs), 1.45-1.9 (5H, m),2.93 (2H, s), 3.5-2.8 (2H, m), 5.2-6.3 (1H, m), 8.50 (2H, s), 6.55 (1H,dd, J = 2.1, 5.8 Hz), 5.95 (1H, d, J = 1.8 Hz), 7.15-7.3 (2H, m), 10.80(1H, s). Fumarate 87 —H

1H-NMR (CDCl3) δ ppm: 1.05-1.85 (15H, m), 2.79 (1H, d, J = 11.8 Hz),2.94 (1H, d, J = 11.6 Hz), 3.45-3.55 (1H, m), 3.6-3.75 (1H, m),6.35-6.45 (1H, m), 6.79 (1H, s), 6.56 (1H, dd, J = 2.1, 8.7 Hz), 7.03(1H, dd, J = 2.4, 3.2 Hz), 7.47 (1H, d, J = 6.7 Hz), 7.89 (1H, br). —

TABLE 15 Absolute configuration

Exam- ple R¹ R⁴ NMR Salt 88 —H

1H-NMR (DMSO-d6) δ ppm: 0.85-1.05 (2H, m), 1.25-1.4 (4H, m), 1.40 (3H,s), 1.5-2.0 (5H, m), 2.82 (1H, d, J = 8.2 Hz), 3.21 (1H, d, J = 12.2Hz), 3.74 (3H, s), 3.8-3.9 (2H, m), 6.44 (1H, dd, J = 2.5, 5.8 Hz),6.5-6.55 (3H, m), 6.95-7.05 (2H, m), 7.22 (1H, d, J = 3.1 Hz). Fumarate89 —H

1H-NMR (DMSO-d6) δ ppm: 1.0-1.2 (2H, m), 1.32 (7H, bs), 1.45-1.55 (8H,m), 2.65-2.95 (2H, m), 3.63 (1H, br), 3.65-3.5 (4H, m), 6.24 (1H, dd, J= 0.6, 3.0 Hz), 8.50 (2H, s), 8.9-7.0 (2H, m), 7.19 (1H, d, J = 3.0 Hz),7.28 (1H, d, J = 8.5 Hz). Fumarate 90 —H

1H-NMR (DMSO-d6) δ ppm: 1.05-1.3 (2H, m), 1.3-1.45 (7H, m), 1.6-1.9 (5H,m), 2.90 (1H, d, J = 12.4 Hz), 3.08 (1H, d, J = 12.3 Hz), 3.62 (1H, br),3.70 (3H, s), 3.8-3.9 (1H, m), 5.25 (1H, d, J = 3.0 Hz), 6.52 (2H, s),6.75-6.85 (2H, m), 7.09 (1H, d, J = 3.1 Hz), 7.35 (1H, d, J = 8.8 Hz).Fumarate 91 —H

1H-NMR (CDCl3) δ ppm: 0.6-2.4 (15H, m), 2.7-3.3 (2H, m), 3.4-3.8 (2H,m), 3.85 (3H, s), 6.95-7.05 (2H, m), 7.15-7.3 (2H, m). —

TABLE 16 Absolute configuration

Exam- ple R¹ R⁴ NMR Salt 92 —H

1H-NMR (DMSO-d6) δ ppm: 1.1-1.4 (9H, m), 1.45-1.75 (4H, m), 1.8-1.95(1H, m), 2.60 (1H, d, J = 12.3 Hz), 3.20 (1H, d, J = 12.3 Hz), 3.4-3.5(1H, m), 3.5-3.9 (1H, m), 8.51 (1H, s), 7.20 (1H, dd, J = 2.5, 9.1 Hz),7.51 (1H, d, J = 2.4 Hz), 7.55 (1H, d, J = 9.1 Hz), 9.01 (1H, s). Hemi-fumarate 93 —H

1H-NMR (DMSO-d6) δ ppm: 1.0-1.2 (2H, m), 1.3-1.45 (1H, m), 1.48 (3H, s),1.58 (3H, s), 1.55-1.7 (1H, m), 1.7-2.15 (6H, m), 2.7-2.95 (5H, m), 3.28(1H, d, J = 12.5 Hz), 3.35-3.45 (1H, m), 3.75-3.95 (1H, m), 6.88 (1H, d,J = 7.8 Hz), 6.90 (1H, d, J = 7.2 Hz), 7.05 (1H, dd, J = 7.6, 7.8 Hz),7.95-8.2 (1H, m), 9.75-10.0 (1H, m). Hydro- chloride 94 —H

1H-NMR (DMSO-d6) δ ppm: 1.15-1.3 (2H, m), 1.3-1.5 (4H, m), 1.53 (3H, s),1.6-1.9 (4H, m), 1.9-2.1 (3H, m), 2.74 (2H, t, J = 7.3 Hz), 2.79 (2H, t,J = 7.4 Hz), 2.93 (1H, d, J = 13.2 Hz), 3.22 (1H, d, J = 13.3 Hz),3.65-3.8 (1H, m), 3.85-4.0 (1H, m), 6.70 (1H, dd, J = 2.2, 8.2 Hz),8.5-5.85 (1H, m), 7.05 (1H, d, J = 8.2 Hz), 7.8-8.4 (2H, m), 9.85-10.2(1H, m). Dihydro- chloride 95 —H

1H-NMR (DMSO-d6) δ ppm: 1.1-1.3 (2H, m), 1.35-1.5 (4H, m), 1.51 (3H, s),1.6-1.9 (4H, m), 2.0-2.1 (1H, m), 2.95 (1H, d, J = 13.0 Hz), 3.02 (1H,d, J = 13.0 Hz), 3.11 (2H, t, J = 8.8 Hz), 3.7-3.85 (2H, m), 4.44 (2H,t, J = 8.6 Hz), 4.7-5.5 (1H, m), 5.6-6.7 (2H, m), 6.85-6.95 (1H, m),6.09 (1H, br), 9.94 (1H, br). Dihydro- chloride

TABLE 17 Absolute configuration

Ex- am- ple R¹ R⁵ R⁶ R⁷ R⁸ R⁹ NMR Salt  96 —H —F —H —H —H —H 1H-NMR(DMSO-d6) δ ppm: 1.1-1.25 (2H, m), 1.35-1.45 (1H, m), 1.46 Hydro- (3H,s), 1.49 (3H, s), 1.6-1.85 (3H, m), 1.85-2.05 (2H, m), 2.93 (1H, d,chloride J = 13.1 Hz), 3.27 (1H, d, J = 13.2 Hz), 3.55-3.65 (1H, m),3.8-3.9 (1H, m), 6.95-7.05 (1H, m), 7.05-7.2 (3H, m), 8.0-8.2 (1H, m),9.55-9.75 (1H, m).  97 —H —H —H —F —H —H 1H-NMR (DMSO-d6) δ ppm:1.1-1.35 (2H, m), 1.35-1.45 (4H, m), 1.53 Dihydro- (3H, s), 1.8-1.95(4H, m), 1.95-2.15 (1H, m), 2.94 (1H, d, J = 13.3 Hz), chloride 3.24(1H, d, J = 13.3 Hz), 3.65-3.85 (1H, m), 3.85-4.0 (1H, m), 4.2-5.5 (1H,m), 8.65-7.0 (2H, m), 7.0-7.1 (2H, m), 8.19 (1H, br), 10.05 (1H, br). 98 —H —H —F —OCH₃ —H —H 1H-NMR (DMSO-d6) δ ppm: 1.2-1.35 (2H, m),1.35-1.45 (4H, m), 1.52 Dihydro- (3H, s), 1.6-1.9 (4H, m), 2.0-2.1 (1H,m), 2.90 (1H, d, J = 13.3 Hz), 3.22 chloride (1H, d, J = 13.2 Hz),3.65-3.8 (4H, m), 3.85-3.95 (1H, m), 8.6-8.7 (1H, m), 6.89 (1H, dd, J =2.9, 14.7 Hz), 7.02 (1H, dd, J = 9.5, 9.5 Hz), 8.05-8.25 (1H, m), 9.94(1H, br).  99 —H —H —OCH₃ —F —H —H 1H-NMR (DMSO-d6) δ ppm: 1.2-1.45 (6H,m), 1.55 (3H, s), 1.6-1.95 Dihydro- (4H, m), 2.0-2.15 (1H, m, 2.95 (1Hd, J = 13.2 Hz), 3.24 (1H, d, J = chloride 13.2 Hz), 3.7-3.8 (1H, m),3.82 (3H, s), 3.9-4.0 (1H, m), 8.4-8.5 (1H, m), 5.70 (1H, dd, J = 2.8,7.6 Hz), 7.03 (1H, dd, J = 8.9, 11.3 Hz), 8.0 (1H, br), 8.15-8.35 (1H,m), 10.0-10.15 (1H, m). 100 —H —F —F —H —H —H 1H-NMR (DMSO-d6) δ ppm:1.15-1.3 (2H, m), 1.35-1.45 (1H, m), 1.46 Hydro- (3H, s), 1.50 (3H, s),1.8-1.85 (3H, m), 1.9-2.05 (2H, m), 3.00 (1H, d, chloride J = 13.2 Hz),3.26 (1H, d, J = 13.2 Hz), 3.5-3.7 (1H, m), 3.5-3.9 (1H, m), 6.85-8.95(1H, m), 6.95-7.05 (1H, m), 7.05-7.15 (1H, m), 8.05-8.35 (1H, m),9.7-9.9 (1H, m). 101 —H —H —H —F —F —H 1H-NMR (DMSO-d6) δ ppm: 1.05-1.4(9H, m), 1.4-1.9 (5H, m), 2.72 Fumarate (1H, d, J = 12.6 Hz), 2.8-4.6(8H, m), 6.54 (2H, s), 6.6-6.7 (1H, m), 6.85-7.0 (1H, m), 7.20 (1H, dd,J = 9.5, 19.9 Hz). 102 —H —H —F —F —F —H 1H-NMR (DMSO-d6) δ ppm:1.25-1.5 (8H, m), 1.51 (3H, s), 1.65-2.1 Hydro- (5H, m), 2.92 (1H, d, J= 13.8 Hz), 3.48 (1H, d, J = 13.8 H), 3.85-3.76 chloride (1H, m),4.0-4.1 (1H, m), 6.8-6.95 (2H, m), 8.15-8.35 (1H, m), 9.85-10.1 (1H, m).103 —H —H —F —OCH₃ —F —H 1H-NMR (DMSO-d6) δ ppm: 1.25-1.55 (9H, m),1.6-1.85 (4H, m), Hydro- 1.85-2.05 (1H, m), 2.90 (1H, d, J = 13.5 Hz),3.48 (1H, d, J = 12.8 Hz), chloride 3.85-3.75 (1H, m), 3.78 (3H, s),3.95-4.05 (1H, m), 6.6-6.8 (2H, m), 6.08 (1H, br), 9.57 (1H, br). 104 —H—Cl —H —H —H —H 1H-NMR (DMSO-d6) δ ppm: 1.0-1.2 (2H, m), 1.3-1.4 (1H,m), 1.48 Hydro- (3H, s), 1.50 (3H, s), 1.6-1.65 (3H, m), 1.85-2.1 (2H,m), 2.74 (1H, chloride d, J = 12.8 Hz), 3.41 (1H, d, J = 13.1 Hz),3.5-3.8 (1H, m), 3.8-3.9 (1H, m), 7.05-7.15 (1H, m), 7.17 (1H, dd, J =1.4, 8.0 Hz), 7.25-7.35 (1H, m), 7.44 (1H, d, J = 1.5, 7.9 Hz), 8.02(1H, br), 9.83 (1H, br). 105 —H —H —Cl —OCH₃ —H —H 1H-NMR (DMSO-d6) δppm: 1.15-1.45 (6H, m), 1.51 (3H, s), 1.5-1.9 Dihydro- (4H, m), 1.95-2.1(1H, m), 2.92 (1H, d, J = 13.3 Hz), 3.20 (1H, d, J = chloride 13.1 Hz),3.7-3.8 (4H, m), 3.9-4.0 (1H, m), 5.9 (1H, br), 6.58 (1H, dd, J = 2.9,9.1 Hz), 7.0-7.06 (1H, m), 6.11 (1H, br), 9.90 (1H, br). 106 —H —H —H—Cl —H —H 1H-NMR (DMSO-d6) δ ppm: 1.2-1.45 (6H, m), 1.51 (3H, s),1.8-2.1 Hydro- (5H, m), 2.93 (1H, d, J = 13.8 Hz), 3.40 (1H, d, J = 13.5Hz), 3.85-3.95 chloride (1H, m), 3.9-4.1 (1H, m), 5.6-7.05 (2H, m),7.1-7.35 (2H, m), 5.14 (1H br), 9.77 (1H, br). 107 —CH₃ —H —H —Cl —H —H1H-NMR (DMSO-d6) δ ppm: 0.98 (3H, s), 1.05-1.2 (4H, m), 1.2-1.45Fumarate (4H, m), 1.55-1.75 (1H, m), 1.55-2.1 (2H, m), 2.18 (3H, s),2.65-4.2 (4H, m), 5.61 (2H, s), 6.8-8.0 (2H, m), 7.1-7.2 (2H, m), 12.8(2H, br). 108 —H —H —OCH₃ —Cl —H —H 1H-NMR (DMSO-d6) δ ppm: 1.2-1.5 (8H,m), 1.5-1.8 (3H, m), 1.6-1.95 Hydro- (4H, m), 2.0-2.1 (1H, m), 2.95 (1H,d, J = 13.5 Hz), 3.3-3.5 (1H, m), chloride 3.7-3.8 (1H, m), 3.84 (3H,s), 4.0-4.1 (1H, m), 6.82 (1H, dd, J = 2.6, 6.9 Hz), 5.63 (1H, d, J =2.5 Hz), 7.19 (1H, d, J = 8.8 Hz), 8.19 (1H, br), 9.75-10.11 (1H, m).109 —H —Cl —Cl —H —H —H 1H-NMR (DMSO-d6) δ ppm: 1.05-1.25 (2H, m),1.35-1.45 (1H, m), 1.47 Hydro- (3H, s), 1.49 (3H, s), 1.6-1.85 (3H, m),1.85-2.05 (2H, m), 2.76 (1H, d, chloride J = 12.8 Hz), 3.42 (1H, d, J =13.0 H), 3.6-3.8 (1H, m), 3.8-3.9 (1H, m), 7.18 (1H, dd, J = 1.6, 7.9Hz), 7.31 (1H, dd, J = 6.0, 8.0 Hz), 7.37 (1H, dd, J = 1.5, 5.0 Hz),6.01 (1H, br), 9.5-9.7 (1H, m). 110 —H —H —Cl —Cl —H —H 1H-NMR (DMSO-d6)δ ppm: 1.2-1.45 (8H, m), 1.52 (3H, s), 1.6-2.15 Hydro- (5H, m), 2.95(1H, d, J = 13.7 Hz), 3.49 (1H, d, J = 13.4 Hz), 3.6-3.8 chloride (1H,m), 3.95-4.15 (1H, m), 6.95 (1H, dd, J = 2.6, 9.1 Hz), 7.05-7.25 (1H,m), 7.40 (1H, d, J = 9.0 Hz), 7.95-8.4 (1H, m), 9.6-10.15 (1H, m). 111—CH₃ —H —Cl —Cl —H —H 1H-NMR (DMSO-d6) δ ppm: 0.98 (3H, s), 1.05-1.2(4H, m), 1.2-1.5 3/2 (4H, m), 1.6-1.75 (1H, m), 1.85-2.05 (2H, m), 2.14(3H, s), 2.75-2.95 Fumarate (2H, m), 3.17 (1H, d, J = 12.4 Hz), 3.7-3.9(1H, m), 5.82 (3H, s), 6.87 (1H, dd, J = 2.9, 9.1 Hz), 7.04 (1H, d, J =2.9 Hz), 7.33 (1H, d, J = 9.0 Hz), 11.0 (3H, br). 112 —H —H —Cl —F —H —H1H-NMR (DMSO-d6) δ ppm: 1.15-1.45 (6H, m), 1.51 (3H, s), 1.6-1.9 Hydro-(4H, m), 1.9-2.05 (1H, s), 2.01 (1H, d, J = 8.2 Hz), 3.3-3.45 (1H, m),chloride 3.85-3.6 (1H, m), 3.95-4.1 (1H, m), 6.85-7.0 (1H, m), 7.12 (1H,dd, J = 3.0, 6.2 Hz), 7,25 (1H, dd, J = 9.1, 9.1 Hz), 8.13 (1H, br),9.86 (1H, br). 113 —H —H —F —Cl —H —H 1H-NMR (DMSO-d6) δ ppm: 1.2-1.45(8H, m), 1.51 (3H, s), 1.6-2.1 Hydro- (5H, m), 2.94 (1H, d, J = 13.7Hz), 3.50 (1H, d, J = 13.6 Hz), 3.65-3.8 chloride (1H, m), 3.95-4.15(1H, m), 5.80 (1H, dd, J = 2.6, 9.1 Hz), 7.01 (1H, dd, J = 2.7, 13.4Hz), 7.34 (1H, dd, J = 9.0, 9.0 Hz), 8.22 (1H, br), 9.90 (1H, br).

TABLE 18 Absolute configuration

Exam- ple R¹ R⁴ NMR Salt 114 —H

1H-NMR (CDCl3) δ ppm: 1.15-1.35 (8H, m), 1.35-1.65 (7H, m), 2.82 (1H, d,J = 11.7 Hz), 3.05 (1H, d, J = 11.7 Hz), 3.45-3.55 (1H, m), 3.7-3.8 (1H,m), 3.65 (3H, s), 6.97 (1H, d, J = 2.3 Hz), 7.03 (1H, d, J = 2.4 Hz),7.08 (1H, dd, J = 2.6, 6.6 Hz), 7.26 (1H, dd, J = 2.8, 9.0 Hz), 7.55(1H, d, J = 8.8 Hz), 7.61 (1H, d, J = 9.0 Hz). — 115 —CH₃

1H-NMR (CDCl3) δ ppm: 1.05 (3H, s), 1.15-1.5 (8H, m), 1.65-1.8 (1H, m),2.0-2.15 (2H, m), 2,18 (3H, s), 2.9-3.0 (2H, m), 3.09 (1H, d, J = 11.7Hz), 3.7-3.8 (1H, m), 3.88 (3H, s), 6.95 (1H, d, J = 2.4 Hz), 7.0-7.1(2H, m), 7.15-7.8 (1H, m), 7.55 (1H, d, J = 8.72 Hz), 7.59 (1H, d, J =9.1 Hz). — 116 —H

1H-NMR (CDCl3) δ ppm: 1.15-1.3 (5H, m), 1.3-1.85 (10H, m), 2.82 (1H, d,J = 11.7 Hz), 3.04 (1H, d, J = 11.7 Hz), 3.45-3.55 (1H, m), 3.7-3.8 (1H,m), 4.11 (2H, q, J = 7.0 Hz), 6.98 (1H, d, J = 2.4 Hz), 7.03 (1H, d, J =2.4 Hz), 7.08 (1H, dd, J = 2.5, 8.8 Hz), 7.2-7.3 (1H, m), 7.56 (1H, d, J= 8.9 Hz), 7.59 (1H, d, J = 9.0 Hz). — 117 —H

1H-NMR (DMSO-d6) δ ppm: 1.25-1.5 (6H, m), 1.57 (3H, s), 1.55-2.15 (5H,m), 3.06 (1H, d, J = 13.4 Hz), 3.47 (1H, d, J = 13.5 Hz), 3.8-3.9 (1H,m), 4.15-4.25 (1H, m), 5.02 (1H, br), 7.24 (1H, d, J = 2.2 Hz), 7.31(1H, ddd, J = 4.5, 12.5, 12.8 Hz), 7.47 (1H, dd, J = 2.2, 9.2 Hz), 7.54(1H, dd, J = 2.6, 10.2 Hz), 7.75-7.8 (2H, m), 8.15-8.3 (1H, m), 9.9-10.0(1H, m). Dihydro- chloride 118 —H

1H-NMR (DMSO-d6) δ ppm: 0.85-1.1 (2H, m), 1.3-1.45 (1H, m), 1.45-1.7(7H, m), 1.7-1.9 (2H, m), 1.8-2.1 (2H, m), 2.81 (1H, d, J = 1.26 Hz),3.45-3.6 (2H, m), 4.15-4.3 (1H, m), 7.12 (1H, d, J = 7.1 Hz), 7.43 (1H,dd, J = 7.6, 7.8 Hz), 7.6-7.8 (2H, m), 7.63 (1H, d, J = 8.2 Hz),7.85-7.95 (1H, m), 8.0-8.2 (1H, m), 8.2-8.3 (1H, m), 9.7-9.95 (1H, m).Hydro- chloride 119 —H

1H-NMR (DMSO-d6) δ ppm: 0.9-1.15 (2H, m), 1.3-1.4 (1H, m), 1.5-1.7 (7H,m), 1.7-1.9 (2H, m), 1.9-2.1 (2H, m), 2.77 (1H, d, J = 12.8 Hz),3.3-3.45 (1H, m), 3.52 (1H, d, J = 12.6 Hz), 4.2-4.3 (1H, m), 7.05-7.15(1H, m), 7.25 (1H, dd, J = 8.2, 10.5 Hz), 7.8-7.7 (2H, m), 8.0-8.2 (2H,m), 8.3-8.4 (1H, m), 9.8-10.0 (1H, m). Hydro- chloride

TABLE 19 Absolute configuration

Example R¹ R⁴ NMR Salt 120 —H

1H-NMR (DMSO-d6) δ ppm: 0.9-1.1 (2H, m), 1.3-1.4 (1H, m), 1.5-1.7 (7H,m), 1.7-1.85 (2H, m), 1.95-2.1 (2H, m), 2.89 (1H, d, J = 12.8 Hz),3.0-3.9 (4H, m), 4.3-4.4 (1H, m), 7.41 (1H, d, J = 7.0 Hz), 7.8-7.9 (1H,m), 7.9-8.0 (2H, m), 8.1-8.2 (1H, m), 9.1-9.25 (2H, m), 9.98 (1H, br).Tri- hydro- chloride 121 —H

1H-NMR (CDCl3) δ ppm: 0.9-1.05 (3H, m), 1.24 (3H, s), 1.35-1.45 (6H, m),1.55-1.8 (3H, m), 1.9-2.05 (1H, m), 2.71 (1H, d, J = 11.3 Hz), 3.25 (1H,d, J = 11.4 Hz), 3.65-3.75 (1H, m), 3.75-3.85 (1H, m), 6.76 (1H, d, J =5.6 Hz), 7.45-7.5 (1H, m), 7.6-7.7 (1H, m), 8.0-5.1 (2H, m), 8.58 (1H,d, J = 5.0 Hz). — 122 —H

1H-NMR (DMSO-d6) δ ppm: 1.35-1.5 (5H, m), 1.61 (3H, s), 1.7-2.0 (3H, m),2.0-2.16 (2H, m), 2.6-4.2 (4H, m), 4.25-4.4 (1H, m), 7.58 (1H, d, J =2.8 Hz), 7.89 (1H, d, J = 5.2, 8.5 Hz), 5.04 (1H, dd, J = 2.7, 9.6 Hz),8.23 (1H, d, J = 9.5 Hz), 8.45-8.8 (1H, m), 8.76 (1H, d, J = 8.3 Hz),5.92 (1H, dd, J = 1.3, 5.2 Hz), 10.21 (1H, d, J = 10.6 Hz). Dihydro-chloride 123 —H

1H-NMR (DMSO-d6) δ ppm: 1.41 (3H, s), 1.45-1.6 (3H, m), 1.63 (3H, s),1.7-1.85 (2H, m), 1.65-2.05 (1H, m), 2.05-2.25 (2H, m), 3.28 (1H, d, J =14.5 Hz), 3.39 (1H, br), 3.75-3.85 (1H, m), 4.10 (1H, d, J = 14.4 Hz),4.4-4.5 (1H, m), 7.61 (1H, d, J = 2.0 Hz), 7.88 (1H, dd, J = 2.4, 9.5Hz), 7.94 (1H, d, J = 8.8 Hz), 5.25-8.35 (2H, m), 8.65-8.85 (1H, m),9.37 (1H, s), 10.3-10.45 (1H, m). Dihydro- chloride

TABLE 20 Absolute configuration

Exam- ple R¹ R⁴ NMR Salt 124 —H

1H-NMR (CDCl3) δ ppm: 0.9-1.15 (2H, m), 1.21 (3H, s), 1.3-1.45 (5H, m),1.45-1.8 (4H, m), 1.8-2.0 (1H, m), 2.64 (1H, d, J = 11.2 Hz), 3.16 (1H,d, J = 11.2 Hz), 3.45-3.65 (1H, m), 3.65-3.75 (1H, m), 6.76 (1H, d, J =7.7 Hz), 7.15-7.3 (1H, m), 7,37 (1H, d, J = 5.5 Hz), 7.45 (1H, d, J =5.5 Hz), 7.51 (1H, d, J = 5.0 Hz). — 125 —CH₃

1H-NMR (DMSO-d6) δ ppm: 0.8-1.05 (2H, m), 1.13 (3H, s), 1.15-1.45 (6H,m), 1.5-1.65 (1H, m), 2.0-2.2 (2H, m), 2.23 (3H, s), 2.81 (1H, d, J =11.6 Hz), 2.8-3.9 (3H, m), 8.51 (4H, s), 6.81 (1H, d, J = 7.6 Hz), 7.24(1H, dd, J = 7.6, 7.8 Hz), 7.45 (1H, d, J = 5.8 Hz), 7.58 (1H, d, J =8.0 Hz), 7.69 (1H, d, J = 5.5 Hz), 13.0 (4H, br). Di- fumarate 126 —H

1H-NMR (DMSO-d6) δ ppm: 1.21-1.35 (2H, m), 1.35-1.6 (4H, m), 1.54 (3H,s), 1.6-2.1 (5H, m), 3.03 (1H, d, J = 18.2 Hz), 3.25-3.4 (1H, m),3.75-3.9 (1H, m), 3.95-4.15 (1H, m), 7.16 (1H, dd, J = 2.2, 5.9 Hz),7.29 (1H, d, J = 5.4 Hz), 7.35 (1H, d, J = 2.1 Hz), 7.68 (1H, d, J = 5.4Hz), 7.82 (1H, d, J = 8.9 Hz), 7.95-8.3 (1H, m), 9.65-9.95 (1H, m).Hydro- chloride 127 —CH₃

1H-NMR (DMSO-d6) δ ppm: 0.95-1.5 (11H, m), 1.56-1.75 (1H, m), 1.55-2.1(2H, m), 2.18 (3H, s), 2.6-4.75 (6H, m), 6.61 (2H, s), 7.10 (1H, dd, J =2.4, 9.0 Hz), 7.24 (1H, d, J = 2.3 Hz), 7.27 (1H, d, J = 6.4 Hz), 7.82(1H, d, J = 6.3 Hz), 7.75 (1H, d, J = 8.9 Hz). Fumarate 128 —H

1H-NMR (DMSO-d6) δ ppm: 1.2-1.5 (6H, m), 1.53 (3H, s), 1.6-2.05 (5H, m),3.08 (1H, d, J = 13.5 Hz), 3.44 (1H, d, J = 13.5 Hz), 3.75-3.9 (1H, m),4.0-4.15 (1H, m), 7.14 (1H, dd, J = 2.2, 8.9 Hz), 7.27 (1H, d, J = 5.4Hz), 7.44 (1H, d, J = 5.4 Hz), 7.48 (1H, d, J = 1.8 Hz), 7.71 (1H, d, J= 8.8 Hz), 7.95-8.2 (1H, m), 9.55-9.5 (1H, m). Hydro- chloride 129 —CH₃

1H-NMR (DMSO-d5) δ ppm: 1.25-1.5 (5H, m), 1.81 (3H, s), 1.85-1.9 (3H,m), 2.05-2.3 (2H, m), 2.74 (3H, d, J = 4.7 Hz), 3.27 (1H, d, J = 13.9Hz), 3.56 (1H, d, J = 13.5 Hz), 3.7-3.85 (1H, m), 4.1-4.25 (1H, m), 7.15(1H, dd, J = 2.3, 5.9 Hz), 7.28 (1H, d, J = 5.4 Hz), 7.44 (1H, d, J =5.4 Hz), 7.49 (1H, d, J = 1.9 Hz), 7.72 (1H, d, J = 8.8 Hz), 9.42 (1H,br). Hydro- chloride 130 —H

1H-NMR (DMSO-d6) δ ppm: 0.95-1.2 (2H, m), 1.3-1.45 (1H, m), 1.53 (8H, s)1.55-1.7 (1H, m), 1.7-1.9 (2H, m), 1.9-2.15 (2H, m), 2.92 (1H, d, J =12.9 Hz), 3.48 (1H, d, J = 12.5 Hz), 3.75-4.0 (2H, m), 7.02 (1H, d, J =7.6 Hz), 7.35 (1H, dd, J = 7.7, 7.7 Hz), 7.48 (1H, d, J = 5.4 Hz), 7.51(1H, d, J = 7.9 Hz), 7.76 (1H, d, J = 5.4 Hz), 8.15 (1H, br), 9.81 (1H,br). Hydro- chloride

TABLE 21 Absolute configuration

Exam- ple R¹ R⁴ NMR Salt 131 —H

1H-NMR (DMSO-d6) δ ppm: 0.95-1.15 (2H, m), 1.3-1.45 (1H, m), 1.52 (3H,s), 1.54 (3H, s), 1.6-2.1 (5H, m), 3.03 (1H, d, J = 13.0 Hz), 3.30 (1H,d, J = 13.4 Hz), 3.75-3.9 (1H, m), 4.0-4.16 (1H, m), 8.95-6.75 (1H, m),7.1-7.25 (3H, m), 7.94 (1H, d, J = 2.2 Hz), 8.0-8.25 (1H, m), 9.7-10.05(1H, m). Hydro- chloride 132 —CH₃

1H-NMR (DMSO-d6) δ ppm: 1.0-1.25 (2H, m), 1.3-1.4 (1H, m), 1.43 (3H, s),1.55-1.9 (6H, m), 2.1-2.35 (2H, m), 2.75 (3H, d, J = 4.7 Hz), 3.21 (1H,d, J = 13.3 Hz), 3.55 (1H, d, J = 13.3 Hz), 3.85-4.1 (2H, m), 6.55-5.75(1H, m), 7.15-7.25 (3H, m), 7.95 (1H, d, J = 2.2 Hz), 9.46 (1H, br).Hydro- chloride 133 —H

1H-NMR (DMSO-d6) δ ppm: 1.1-1.35 (2H, m), 1.35-1.5 (4H, m), 1.55 (3H,s), 1.8-1.95 (4H, m), 1.95-2.1 (1H, m), 3.03 (1H, d, J = 13.1 Hz), 3.20(1H, d, J = 12.9 Hz), 3.75-3.9 (1H, m), 3.0-4.0 (1H, m), 5.29 (1H, br),6.8-6.85 (1H, m), 7.03 (1H, dd, J = 2.4, 9.0 Hz), 7.13 (1H, d, J = 2.3Hz), 7.45 (1H, d, J = 9.0 Hz), 7.89 (1H, d, J = 2.2 Hz), 8.15 (1H, br),9.99 (1H, br). Dihydro- chloride 134 —H

1H-NMR (DMSO-d6) δ ppm: 1.2-1.5 (8H, m), 1.56 (3H, s), 1.6-2.0 (4H, m),2.0-2.15 (1H, m), 3.01 (1H, d, J = 13.4 Hz), 3.35 (1H, d, J = 13.3 Hz),3.65-3.85 (1H, m), 3.95-4.15 (1H, m), 6.75-6.55 (1H, m), 6.98 (1H, dd, J= 2.1, 8.7 Hz), 7.13 (1H, s), 7.47 (1H, d, J = 8.6 Hz), 7.5-8.0 (2H, m),8.15-8.35 (1H, m), 10.0-10.2 (1H, m). Dihydro- chloride 135 —H

1H-NMR (DMSO-d6) δ ppm: 1.1-1.3 (2H, m), 1.35-1.45 (1H, m), 1.50 (3H,s), 1.56 (3H, s), 1.6-1.9 (3H, m), 1.9-2.1 (2H, m), 3.2-3.4 (2H, m),3.85-4.0 (1H, m), 4.15-4.25 (1H, m), 8.80 (1H, d, J = 7.0 Hz), 6.94 (1H,d, J = 2.2 Hz), 7.12 (1H, dd, J = 7.7, 7.7 Hz), 7.21 (1H, dd, J = 0.8,7.7 Hz), 7.97 (1H, d, J = 2.2 Hz), 6.1-6.35 (1H, m), 9.75-9.95 (1H, m).Hydro- chloride 136 —H

1H-NMR (CDCl3) δ ppm: 1.0-1.45 (11H, m), 1.6-1.8 (3H, m), 1.8-1.95 (1H,m), 2.70 (1H, d, J = 11.3 Hz), 3.04 (1H, d, J = 11.4 Hz), 3.45-3.55 (1H,m), 3.55-3.65 (1H, m), 6.47 (1H, dd, J = 3.4, 6.6 Hz), 6.64 (1H, dd, J =2.5, 2.6 Hz), 6.89 (1H, dd, J = 8.6, 10.4 Hz), 7.60 (1H, d, J = 2.1 Hz).— 137 —H

1H-NMR (CDCl3) δ ppm: 1.0-1.15 (2H, m), 1.20 (3H, s), 1.25-1.45 (6H, m),1.6-1.8 (3H, m), 1.8-1.95 (1H, m), 2.79 (1H, d, J = 11.5 Hz), 3.05 (1H,d, J = 11.4 Hz), 3.55-3.65 (2H, m), 6.53 (1H, d, J = 6.4 Hz), 6.64 (1H,d, J = 2.2 Hz), 7.14 (1H, d, J = 6.4 Hz), 7.61 (1H, d, J = 2.2 Hz). —138 —H

1H-NMR (DMSO-d6) δ ppm: 0.95-1.1 (2H, m), 1.3-1.4 (1H, m), 1.51 (3H, s),1.53 (3H, s), 1.6-1.7 (1H, m), 1.7-2.0 (3H, m), 2.0-2.05 (1H, m), 2.39(3H, s), 2.95 (1H, d, J = 12.6 Hz), 3.28 (1H, d, J = 12.9 Hz), 3.7-3.8(1H, m), 4.0-4.15 (1H, m), 6.61 (1H, d, J = 7.9 Hz), 6.99 (1H, d, J =6.1 Hz), 7.20 (1H, d, J = 2.2 Hz), 7.95 (1H, d, J = 2.2 Hz), 8.0-8.15(1H, m), 9.57-9.95 (1H, m). Hydro- chloride 139 —H

1H-NMR (DMSO-d6) δ ppm: 0.9-1.1 (2H, m), 1.3-1.4 (1H, m), 1.52 (6H, s),1.55-1.65 (1H, m), 1.85-1.95 (3H, m), 1.95-2.1 (1H, m), 2.96 (1H, d, J =12.8 Hz), 3.27 (1H, d, J = 12.8 Hz), 3.6-3.7 (1H, m), 3.87 (3H, s),4.0-4.15 (1H, m), 6.61 (1H, d, J = 8.4 Hz), 6.79 (1H, d, J = 8.4 Hz),7.21 (1H, d, J = 2.2 Hz), 7.95 (1H, d, J = 2.1 Hz), 7.95-8.15 (1H, m),9.7-9.9 (1H, m). Hydro- chloride 140 —H

1H-NMR (DMSO-d6) δ ppm: 1.05-1.25 (2H, m), 1.35-1.45 (1H, m), 1.50 (3H,s), 1.54 (3H, s), 1.8-1.9 (3H, m), 1.9-2.1 (2H, m), 3.17 (1H, d, J =13.1 Hz), 3.29 (1H, d, J= 13.2 Hz), 3.9-4.0 (1H, m), 4.0-4.1 (1H, m),6.60 (1H, dd, J = 4.4, 8.7 Hz), 5.98 (1H, dd, J = 8.9, 5.9 Hz), 7.06(1H, d, J = 2.2 Hz), 8.08 (1H, d, J = 2.2 Hz), 8.1-8.3 (1H, m),9.75-9.95 (1H, m). Hydro- chloride

TABLE 22 Absolute configuration

Ex- am- ple R¹ R⁴ NMR Salt 141 —H

1H-NMR (CDCl3) δ ppm: 1.1-1.2 (20H, m), 1.20 (3H, s), 1.3-1.46 (6H, m),1.55-1.8 (6H, m), 1.8-2.0 (1H, m), 2.83 (1H, d, J = 11.5 Hz), 3.11 (1H,d, J = 11.6 Hz), 3.6-5.7 (1H, m), 3.7-3.8 (1H, m), 6.50 (1H, d, J = 7.5Hz), 5.64 (1H, d, J = 3.2 Hz), 7.00 (1H, dd, J = 7.9, 7.9 Hz), 7.11 (1H,d, J = 6.3 Hz), 7.16 (1H, d, J = 3.7 Hz). — 142 —H

1H-NMR (CDCl3) δ ppm: 1.13 (18H, d, J = 7.5 Hz), 1.21 (3H, s), 1.28 (3H,s), 1.3-1.6 (5H, m), 1.6-1.8 (7H, m), 2.80 (1H, d, J = 11.7 Hz), 2.93(1H, d, J = 11.6 Hz), 3.46-3.56 (1H, m), 3.55-3.85 (1H, m), 6.48 (1H,dd, J = 0.7, 3.1 Hz), 6.85 (1H, dd, J = 2.4, 9.0 Hz), 7.02 (1H, d, J =2.3 Hz), 7.16 (1H, d, J = 3.1 Hz), 7.36 (1H, d, J = 9.0 Hz). —

TABLE 23 Absolute configuration

Example R¹ R⁴ NMR Salt 143 —H

1H-NMR (CDCl3) δ ppm: 0.9-1.15 (2H, m), 1.21 (3H, s), 1.25-1.45 (5H, m),1.45-1.8 (4H, m), 1.8-2.0 (1H, m), 2.83 (1H, d, J = 11.5 Hz), 3.11 (1H,d, J = 11.5 Hz), 3.6-3.75 (1H, m), 3.75-3.9 (1H, m), 8.50 (1H, d, J =7.3 Hz), 6.58-6.65 (1H, m), 7.00 (1H, d, J = 8.0 Hz), 7.07 (1H, dd, J =7.7, 7.7 Hz), 7.14 (1H, dd, J = 2.8, 2.8 Hz), 8.16 (1H, br). — 144 —H

1H-NMR (DMSO-d6) δ ppm: 1.0-1.25 (2H, m), 1.33 (7H, bs), 1.45-1.9 (5H,m), 2.6-3.0 (2H, m), 3.0-4.05 (5H, m), 6.2-6.3 (1H, m), 6.50 (2H, s),6.86 (1H, dd, J = 2.2, 8.8 Hz), 6.95 (1H, d, J = 1.9 Hz), 7.15-7.3 (2H,m), 10.79 (1H, s). Fumarate 145 —H

1H-NMR (DMSO-d6) δ ppm: 0.55-1.05 (2H, m), 1.25-1.4 (4H, m), 1.42 (3H,s), 1.5-2.0 (5H, m), 2.54 (1H, d, J = 12.3 Hz), 3.24 (1H, d, J = 12.3Hz), 3.74 (3H, s), 3.8-3.95 (2H, m), 6.45 (1H, dd, J = 2.2, 6.2 Hz),6.5-6.55 (3H, m), 6.95-7.05 (2H, m), 7.23 (1H, d, J = 3.1 Hz). Fumarate146 —CH₃

1H-NMR (CDCl3) δ ppm: 1.0-1.5 (11H, m), 1.6-1.7 (1H, m), 2.05-2.3 (5H,m), 2.75 (1H, d, J = 11.4 Hz), 3.05-3.15 (1H, m), 3.36 (1H, d, J = 11.5Hz), 3.75 (3H, s), 3.8-3.9 (1H, m), 6.45-6.55 (2H, m), 6.92 (1H, d, J =8.2 Hz), 8.96 (1H, d, J = 3.1 Hz), 7.10 (1H, dd, J = 0.7, 3.1 Hz). — 147—H

1H-NMR (DMSO-d6) δ ppm: 1.0-1.2 (2H, m), 1.33 (7H, bs), 1.45-1.55 (8H,m), 2.85-2.95 (2H, m), 3.64 (1H, br), 3.7-3.8 (4H, m), 6.24 (1H, dd, J =0.7, 3.0 Hz), 8.51 (2H, s), 6.9-7.0 (2H, m), 7.19 (1H, d, J = 3.0 Hz),7.28 (1H, d, J = 6.6 Hz). Fumarate 148 —H

1H-NMR (DMSO-d6) δ ppm: 1.05-1.3 (2H, m), 1.3-1.45 (7H, m), 1.5-1.9 (5H,m), 2.93 (1H, d, J = 12.3 Hz), 5.09 (1H, d, J = 12.4 Hz), 3.65 (1H, br),3.70 (3H, s), 3.6-3.95 (1H, m), 6.25 (1H, d, J = 3.0 Hz), 6.51 (2H, s),6.75-6.85 (2H, m), 7.09 (1H, d, J = 3.1 Hz), 7.36 (1H, d, J = 9.2 Hz).Fumarate 149 —CH₃

1H-NMR (CDCl3) δ ppm: 1.06 (3H, s), 1.1-1.5 (8H, m), 1.65-1.75 (1H, m),2.0-2.15 (2H, m), 2.18 (3H, s), 2.67 (1H, d, J = 11.4 Hz), 2.95-3.0 (1H,m), 3.10 (1H, d, J = 11.4 Hz), 3.65-3.75 (4H, m), 6.34 (1H, dd, J = 0.7,3.1 Hz), 5.62 (1H, d, J = 1.6 Hz), 6.8-6.9 (2H, m), 7.44 (1H, d, J = 8.7Hz). — 150 —H

1H-NMR (CDCl3) δ ppm: 0.7-2.3 (16H, m), 2.7-3.2 (2H, m), 3.5-3.8 (2H,m), 3.65 (3H, s), 8.95-7.05 (2H, m), 7.15-7.3 (2H, m). —

TABLE 24 Absolute configuration

Exam- ple R¹ R⁴ NMR Salt 151 —H

1H-NMR (DMSO-d6) δ ppm: 1.1-1.4 (9H, m), 1.45-1.6 (4H, m), 1.8-1.95 (1H,m), 2.81 (1H, d, J = 12.3 Hz), 3.22 (1H, d, J = 12.4 Hz), 3.45-3.5 (1H,m), 3.85-3.95 (1H, m), 6.52 (1H, s), 7.20 (1H, dd, J = 2.5, 9.1 Hz),7.51 (1H, d, J = 2.4 Hz), 7.85 (1H, d, J = 9.1 Hz), 9.02 (1H, s). Hemi-fumarate 152 —H

1H-NMR (DMSO-d6) δ ppm: 1.0-1.2 (2H, m), 1.5-1.45 (1H, m), 1.48 (3H, s),1.50 (3H, s), 1.55-1.7 (1H, m), 1.7-2.15 (5H, m), 2.7-2.95 (5H, m), 3.28(1H, d, J = 12.8 Hz), 3.35-3.45 (1H, m), 3.8-3.9 (1H, m), 6.88 (1H, d, J= 7.6 Hz), 6.90 (1H, d, J = 7.3 Hz), 7.05 (1H, dd, J = 7.6, 7.6 Hz),7.95-8.2 (1H, m), 9.7-9.95 (1H, m). Hydro- chloride 153 —H

1H-NMR (DMSO-d6) δ ppm: 1.15-1.3 (2H, m), 1.35-1.5 (4H, m), 1.53 (3H,s), 1.8-1.9 (4H, m), 1.9-2.1 (3H, m), 2.74 (2H, t, J = 7.3 Hz), 2.79(2H, t, J = 7.4 Hz), 2.93 (1H, d, J = 13.3 Hz), 3.22 (1H, d, J = 13.3Hz), 3.65-3.5 (1H, m), 3.85-4.0 (1H, m), 8.70 (1H, dd, J = 2.2, 8.2 Hz),8.8-8.85 (1H, m), 7.05 (1H, d, J = 8.2 Hz), 7.33 (1H, br), 8.0-8.3 (1H,m), 9.9-10.01 (1H, m). Dihydro- chloride 154 —H

1H-NMR (DMSO-d6) δ ppm: 1.1-1.3 (2H, m), 1.35-1.5 (4H, m), 1.52 (3H, s),1.6-1.9 (4H, m), 2.0-2.1 (1H, m), 2.95 (1H, d, J = 13.0 Hz), 3.02 (1H,d, J = 15.0 Hz), 3.11 (2H, t, J = 8.8 Hz), 3.7-3.85 (2H, m), 4.44 (2H,t, J = 8.8 Hz), 5.96 (1H, br), 6.6-6.7 (2H, m), 6.85-6.95 (1H, m),6.0-6.25 (1H, m), 9.9-10.2 (1H, m). Dihydro- chloride

TABLE 25 Absolute configuration

Ex- am- ple R¹ R⁵ R⁶ R⁷ R⁸ R⁹ NMR Salt 155 —H —F —H —H —H —H 1H-NMR(DMSO-d6) δ ppm: 1.1-1.25 (2H, m), 1.3-1.56 (1H, m), 1.46 Hydro- (3H,s), 1.49 (3H, s). 1.65-1.85 (3H, m), 1.85-2.05 (2H, m), 2.98 (1H,chloride d, J = 13.0 Hz), 3.27 (1H, d, J = 13.1 Hz), 3.55-3.65 (1H, m),3.8-3.9 (1H, m), 6.95-7.05 (1H, m), 7.05-7.2 (8H, m), 5.08 (1H, br),9.55 (1H, br) 156 —H —H —H —F —H —H 1H-NMR (DMSO-d6) δ ppm: 1.15-1.45(8H, m), 1.52 (3H, s), 1.8-2.15 Dihydro- (5H, m), 2.94 (1H, d, J = 13.3Hz), 3.25 (1H, d, J = 13.1 Hz), 3.95-3.4 chloride (3H, m), 6.85-7.0 (2H,m), 7.0-7.1 (2H, m), 6.16 (1H, br), 9.94 (1H, br). 157 —CH₃ —H —H —F —H—H 1H-NMR (DMSO-d6) δ ppm: 0.99 (3H, s), 1.0-1.1 (1H, m), 1.15 (3H,Fumarate s), 1.2-1.45 (4H, m), 1.55-1.7 (1H, m), 1.85-2.05 (2H, s), 2.15(3H, s), 2.35-4.55 (4H, m), 6.59 (2H, s), 6.8-6.9 (2H, m), 6.9-7.05 (2H,m), 12.9 (2H, br). 158 —H —H —F —OCH₃ —H —H 1H-NMR (DMSO-d6) δ ppm:1.2-1.35 (2H, m), 1.35-1.45 (4H, m), 1.51 Hydro- (3H, s), 1.6-1.9 (4H,m), 1.95-2.1 (1H, m), 2.90 (1H, d, J = 13.4 Hz), chloride 3.22 (1H, d, J= 13.3 Hz), 3.55-3.8 (4H, m), 3.85-3.95 (1H, m), 6.6-6.7 (1H, m), 6.89(1H, dd, J = 2.9, 14.7 Hz), 7.02 (1H, dd, J = 9.5, 9.5 Hz), 8.12 (1H,m), 9.90 (1H, br). 159 —H —H —OCH₃ —F —H —H 1H-NMR (DMSO-d6) δ ppm:1.2-1.5 (6H, m), 1.54 (3H, s), 1.6-1.95 Hydro- (4H, m), 2.0-2.15 (1H,m), 2.95 (1H, d, J = 13.3 Hz), 3.24 (1H, d, J = chloride 13.2 Hz),3.7-3.8 (1H, m), 3.82 (3H, s), 3.9-4.05 (1H, m), 6.4-6.5 (1H, m), 6.70(1H, dd, J = 2.8, 7.6 Hz), 7.03 (1H, dd, J = 6.9, 11.3 Hz), 7.65 (1H,br), 6.15-6.35 (1H, m), 10.0-10.15 (1H, m). 160 —H —F —F —H —H —H 1H-NMR(DMSO-d6) δ ppm: 1.15-1.3 (2H, m), 1.35-1.45 (1H, m), 1.46 Hydro- (3H,s), 1.50 (3H, s), 1.6-1.85 (4H, m), 1.9-2.05 (3H, m), 3.00 (1H, d,chloride J = 13.2 Hz), 3.28 (1H, d, J = 13.4 Hz), 3.6-3.7 (1H, m),3.8-3.9 (1H, m), 6.85-6.95 (1H, m), 6.95-7.05 (1H, m), 7.05-7.15 (1H,m), 8.1-8.3 (1H, m), 9.7-9.9 (1H, m). 161 —H —H —F —F —H —H 1H-NMR(DMSO-d6) δ ppm: 1.2-1.5 (6H, m), 1.52 (3H, s), 1.6-2.15 Hydro- (5H, m),2.93 (1H, d, J = 13.5 Hz), 3.2-3.45 (1H, m), 3.65-3.8 (1H, m), chloride3.9-4.1 (1H, m), 6.85-6.8 (1H, m), 6.95-7.1 (1H, m), 7.25 (1H, dd, J =9.4, 19.8 Hz), 6.0-6.35 (1H, m), 9.75-10.1 (1H, m). 162 —CH₃ —H —F —F —H—H 1H-NMR (DMSO-d6) δ ppm: 0.97 (3H, s), 1.06-1.2 (4H, m), 1.2-1.45Fumarate (4H, m), 1.6-1.75 (1H, m), 1.85-2.05 (2H, s), 2.14 (3H, s),2.85-4.05 (4H, m), 8.55-8.7 (3H, m), 6.8-6.95 (1H, m), 7.18 (1H, dd, J =9.5, 20.0 Hz), 13.0 (2H, br). 163 —H —H —F —F —F —H 1H-NMR (DMSO-d6) δppm: 1.25-1.5 (6H, m), 1.50 (3H, s), 1.85-1.9 Hydro- (4H, m), 1.95-2.05(1H, m), 2.92 (1H, dd, J = 13.8 Hz), 3.47 (1H, d, J = chloride 13.8 Hz),3.65-3.8 (1H, m), 4.0-4.1 (1H, m), 6.8-6.95 (2H, m), 6.1-8.3 (1H, m),9.75-9.95 (1H, m). 164 —H —H —F —OCH₃ —F —H 1H-NMR (DMSO-d6) δ ppm:1.2-1.45 (6H, m), 1.50 (3H, s), 1.6-1.9 Hydro- (4H, m), 1.9-2.1 (1H, m),2.90 (1H, d, J = 13.6 Hz), 3.42 (1H, d, J = chloride 13.5 Hz), 3.6-3.75(1H, m), 3.78 (3H, s), 3.95-4.05 (1H, m), 6.6-6.85 (2H, m), 8.16 (1H,br), 9.85 (1H, br). 165 —H —Cl —H —H —H —H 1H-NMR (DMSO-d6) δ ppm:1.0-1.2 (2H, m), 1.3-1.45 (1H, m), 1.49 Hydro- (3H, s), 1.51 (3H, s),1.6-1.85 (3H, m), 1.9-2.1 (2H, m), 2.73 (1H, d, chloride J = 12.6 Hz),3.41 (1H, d, J = 12.8 Hz), 3.45-3.55 (1H, m), 3.75-3.9 (1H, m),7.05-7.15 (1H, m), 7.17 (1H, dd, J = 1.4, 8.0 Hz), 7.25-7.35 (1H, m),7.44 (1H, d, J = 1.4, 8.0 Hz), 8.09 (1H, br), 9.7-9.9 (1H, m). 166 —H —H—Cl —OCH₃ —H —H 1H-NMR (DMSO-d6) δ ppm: 1.15-1.45 (6H, m), 1.52 (3H, s),1.6-1.9 Dihydro- (4H, m), 2.0-2.1 (1H, m), 2.82 (1H, d, J = 13.2 Hz),3.19 (1H, d, J = chloride 13.1 Hz), 3.7-3.8 (4H, m), 3.85-3.95 (1H, m),5.9 (1H, br), 6.88 (1H, dd, J = 2.9, 9.0 Hz), 7.0-7.05 (1H, m), 8.15(1H, br), 10.00 (1H, br). 167 —H —H —H —Cl —H —H 1H-NMR (DMSO-d6) δ ppm:1.2-1.45 (6H, m), 1.51 (3H, s), 1.6-2.1 Hydro- (5H, m), 2.93 (1H, d, J =13.7 Hz), 3.2-3.5 (1H, m), 3.65-3.85 (1H, m), chloride 3.9-4.1 (1H, m),6.96 (2H, d, J = 9.0 Hz), 7.24 (2H, d, J = 8.9 Hz), 8.14 (1H, br),9.45-10.0 (1H, m). 168 —CH₃ —H —H —Cl —H —H 1H-NMR (DMSO-d6) δ ppm: 0.97(3H, s) 1.05-1.2 (4H, m), 1.2-1.45 Fumarate (4H, m), 1.8-1.75 (1H, m),1.85-2.05 (2H, m), 2.14 (3H, s), 2.85-4.35 (4H, m), 6.61 (2H, s),6.8-6.9 (2H, m), 7.1-7.2 (2H, m), 12.9 (2H, br). 169 —H —Cl —Cl —H —H —H1H-NMR (DMSO-d6) δ ppm: 1.05-1.25 (2H, m), 1.35-1.45 (1H, m), Hydro-1.47 (3H, s), 1.49 (3H, s), 1.6-1.65 (3H, m), 1.9-2.05 (2H, m), 2.76chloride (1H, d, J = 12.8 Hz), 3.42 (1H, d, J = 13.0 Hz), 3.5-3.6 (1H,m), 3.8-3.9 (1H, m), 7.18 (1H, dd, J = 1.6, 7.9 Hz), 7.31 (1H, dd, J =8.0, 8.0 Hz), 7.37 (1H, dd, J = 1.5, 8.0 Hz), 6.02 (1H, br), 9.81 (1H,br). 170 —H —H —Cl —Cl —H —H 1H-NMR (DMSO-d6) δ ppm: 1.2-1.45 (6H, m),1.51 (3H, s), 1.8-2.1 Hydro- (5H, m), 2.95 (1H, d, J = 13.7 Hz), 3.49(1H, d, J = 13.7 Hz), 3.85-3.8 chloride (1H, m), 4.0-4.15 (1H, m), 6.95(1H, d, J = 3.0, 9.1 Hz), 7.16 (1H, d, J = 2.9 Hz), 7.40 (1H, d, J = 9.0Hz), 7.95-6.35 (1H, m), 9.6-10.05 (1H, m). 171 —CH₃ —H —Cl —Cl —H —H1H-NMR (DMSO-d6) δ ppm: 0.95 (3H, s), 1.05-1.2 (4H, m), 1.2-1.5 3/2 (4H,m), 1.56-1.75 (1H, m), 1.85-2.05 (2H, m), 2.13 (3H, s), 2.75-2.9Fumarate (2H, m), 3.17 (1H, d, J = 12.4 Hz), 3.75-3.85 (1H, m), 6.62(3H, s), 6.57 (1H, dd, J = 2.9. 9.1 Hz), 7.04 (1H, d, J = 2.9 Hz), 7.33(1H, d, J = 9.0 Hz), 11.0 (3H, br). 172 —H —H —Cl —F —H —H 1H-NMR(DMSO-d6) δ ppm: 1.1-1.45 (5H, m), 1.50 (3H, s), 1.6-1.9 Hydro- (4H, m),1.9-2.1 (1H, s), 2.00 (1H, d, J = 8.2 Hz), 3.25-3.45 (1H, m), chloride3.65-3.85 (1H, m), 3.9-4.1 (1H, m), 6.55-7.0 (1H, m), 7.12 (1H, dd, J =3.0, 6.3 Hz), 7.25 (1H, dd, J = 9.1, 9.1 Hz), 8.12 (1H, br), 9.82 (1H,br). 173 —H —H —F —Cl —H —H 1H-NMR (DMSO-d6) δ ppm: 1.2-1.45 (6H, m),1.50 (3H, s), 1.6-2.1 Hydro- (5H, m), 2.94 (1H, d, J = 13.8 Hz), 3.51(1H, d, J = 13.9 Hz), 3.65-3.85 chloride (1H, m), 3.95-4.15 (1H, m),6.80 (1H, dd, J = 2.5, 8.9 Hz), 7.01 (1H, dd J = 2.8, 13.4 Hz), 7.34(1H, dd, J = 9.0, 9.0 Hz), 8.16 (1H, br), 9.77 (1H, br). 174 —H —H —OCH₃—Cl —H —H 1H-NMR (DMSO-d6) δ ppm: 1.2-1.5 (8H, m), 1.53 (3H, s),1.65-1.95 Hydro- (4H, m), 1.95-2.1 (1H, m), 2.95 (1H, d, J = 13.6 Hz),3.3-3.45 (1H, m), chloride 3.7-3.8 (1H, m), 3.64 (3H, s), 4.0-4.1 (1H,m), 6.52 (1H, dd, J = 2.7, 5.9 Hz), 6.63 (1H, d, J = 2.6 Hz), 7.19 (1H,d, J = 8.8 Hz), 8.16 (1H, br), 9.86 (1H, br).

TABLE 26 Relative configuration

Example R¹ R⁴ NMR Salt 175 —H

1H-NMR (CDCl3) δ ppm: 1.04-1.21 (1H, m), 1.25-1.45 (2H, m), 1.64-1.88(3H, m), 1.87 (3H, s), 1.77 (3H, s), 2.00-2.12 (1H, m), 2.34-2.40 (1H,m), 2.88 (1H, d, J = 12.5 Hz), 3.13-3.29 (2H, m), 3.42 (1H, d, J = 12.5Hz), 7.29-7.34 (1H, m), 7.41-7.51 (2H, m), 7.60 (1H, s), 7.77-7.82 (3H,m), 9.51 (1H, brs), 9.79 (1H, brs) Hydro- chloride 176 —H

1H-NMR (CDCl3) δ ppm: 1.00-1.11 (1H, m), 1.25-1.39 (2H, m), 1.58-1.81(3H, m), 1.85 (3H, s), 1.75 (3H, s), 1.96-2.10 (1H, m), 2.32-2.37 (1H,m), 2.82 (1H, d, J = 12.5 Hz), 3.08-3.15 (1H, m), 3.18-3.36 (2H, m),3.39 (1H, d, J = 12.5 Hz), 7.19 (1H, d, J = 8.5 Hz), 7.29 1H, d, J = 5.4Hz), 7.47 (1H, d, J = 5.4 Hz), 7.84 (1H, s), 7.81 (1H, d, J = 8.5 Hz),9.46 (1H, brs), 9.75 (1H, brs) Hydro- chloride 177 —H

1H-NMR (DMSO) δ ppm: 0.92-1.37 (3H, m), 1.27 (3H, s), 1.40-1.60 (3H, m),1.52 (3H, s), 1.80-1.75 (1H, m), 1.80-1.90 (1H, m), 2.60-2.73 (1H, m),2.78 (1H, d, J = 12.1 Hz), 2.97 (1H, d, J = 12.1 Hz), 3.00-3.12 (1H, m),3.13-3.89 (3H, br), 3.76 (3H, s), 5.36 (1H, d, J = 3.0 Hz), 6.50 (2H,s), 6.94 (1H, dd, J = 8.6, 1.8 Hz), 7.28 (1H, d, J = 1.6 Hz), 7.30 (1H,d, J = 3.0 Hz), 7.36 (1H, d, J = 8.6 Hz) Fumarate 178 —H

1H-NMR (CDCl3) δ ppm: 0.97-1.09 (1H, m), 1.23-1.35 (2H, m), 1.62-1.63(3H, m), 1.63 (3H, s), 1.86 (3H, s), 1.92-2.05 (1H, m), 2.29-2.36 (1H,m), 2.73 (1H, d, J = 12.4 Hz), 2.94-3.03 (1H, m), 3.11-3.22 (1H, m),3.28 (1H, d, J = 12.4 Hz), 7.02 (1H, dd, J = 8.5, 2.4 Hz), 7.25 (1H, d,J = 2.4 Hz), 7.39 (1H, d, J = 8.5 Hz), 9.50 (1H, brs), 9.78 (1H, brs)Hydro- chloride

TABLE 27 Absolute configuration

Ex- am- ple R¹ R⁴ NMR Salt 179 —H

1H-NMR (CDCl3) δ ppm: 1.26-2.30 (6H, m), 1.79 (3H, s), 2.17 (3H, s),2.51-2.57 (1H, m), 3.36 (1H, d, J = 13.2 Hz), 3.90-4.30 (2H, m), 4.08(1H, d, J = 13.2 Hz), 7.66-7.69 (2H, m), 7.83-8.01 (4H, m), 6.50 (1H,brs), 10.07 (1H, brs), 10.26 (1H, brs) Dihydro- chloride 180 —CH₃

1H-NMR (CDCl3) δ ppm: 1.20-1.36 (1H, m), 1.42-1.75 (4H, m), 1.76 (3H,s), 1.91-1.93 (1H, m), 2.03-2.18 (1H, m), 2.16 (3H, s), 2.30-2.53 (2H,m), 2.85 (3H, d, J = 4.9 Hz), 3.49 (1H, d, J = 13.6 Hz), 4.05-4.21 (1H,m), 4.68 (1H, d, J = 13.6 Hz), 4.95-5.06 (1H, m), 7.55-7.67 (2H, m),7.59-8.05 (4H, m), 8.95 (1H, br), 13.17 (1H, brs) Dihydro- chloride 181—H

1H-NMR (DMSO-d6) δ ppm: 0.94-1.25 (2H, m), 1.25-1.45 (5H, m), 1.45-1.55(1H, m), 1.55-1.80 (5H, m), 1.95-2.10 (1H, m), 2.82 (1H, d, J = 12.4Hz), 2.97-3.11 (2H, m), 3.36-3.51 (1H, m), 7.40 (1H, d, J = 7.3 Hz),7.50-7.59 (3H, m), 7.79 (1H, d, J = 8.2 Hz), 7.89-7.96 (1H, m),8.42-8.48 (1H, m), 8.97-9.24 (1H, br), 9.50-9.80 (1H, br). Hydro-chloride 182 —H

1H-NMR (CDCl3) δ ppm: 1.21-2.12 (8H, m), 1.77 (3H, s), 2.11 (3H, s),2.49-2.55 (1H, m), 3.27 (1H, d, J = 13.1 Hz), 3.64-4.22 (3H, m), 3.94(3H, s), 7.15-7.24 (2H, m), 7.68-7.85 (3H, m), 8.25 (1H, brs), 10.04(2H, brs) Dihydro- chloride 183 —CH₃

1H-NMR (CDCl3) δ ppm: 1.20-1.50 (2H, m), 1.63-2.25 (7H, m), 1.70 (3H,s), 1.95 (3H, s), 2.51 (3H, d, J = 4.9 Hz), 3.27 (1H, d, J = 13.2 Hz),3.49-3.86 (1H, m), 3.94 (3H, s), 4.22-4.70 (2H, br), 7.14-7.25 (2H, m),7.68-7.82 (3H, m), 7.97-8.60 (1H, br), 12.21 (1H, brs) Dihydro- chloride184 —H

1H-NMR (DMSO-d6) δ ppm: 1.01-1.48 (6H, m), 1.48-1.85 (7H, m), 1.95-2.12(1H, m), 2.88-3.33 (4H, m), 4.45-5.45 (1H, br), 7.30-7.48 (2H, m),7.62-7.75 (2H, m), 7.89 (1H, d, J = 8.8 Hz), 7.99 (1H, dd, J = 5.6, 9.1Hz), 9.07-9.38 (1H, br), 9.60-9.88 (1H, br). Dihydro- chloride

TABLE 28 Absolute configuration

Ex- am- ple R¹ R⁴ NMR Salt 185 —H

1H-NMR (CDCl3) δ ppm: 0.96-1.07 (1H, m), 1.25-1.33 (2H, m), 1.48-1.86(3H, m), 1.85 (3H, s), 1.85 (3H, s), 1.95-2.12 (1H, m), 2.37-2.42 (1H,m), 2.88 (1H, d, J = 12.7 Hz), 3.20-3.35 (2H, m), 3.32 (1H, d, J = 12.7Hz), 7.26 (1H, d, J = 7.7 Hz), 7.35 (1H, dd, J = 7.7, 7.7 Hz), 7.41 (1H,d, J = 5.5 Hz), 7.53 (1H, d, J = 5.6 Hz), 7.72 (1H, d, J = 7.7 Hz), 9.57(1H, brs), 9.87 (1H, brs) Hydro- chloride 186 —H

1H-NMR (CDCl3) δ ppm: 1.18-2.18 (8H, m), 1.78 (3H, s), 2.17 (3H, s),2.47-2.54 (1H, m), 8.28 (1H, d, J = 12.9 Hz), 3.72-4.05 (2H, m), 3.92(1H, d, J = 12.9 Hz), 7.41 (1H, d, J = 5.5 Hz), 7.59 (1H, d, J = 5.5Hz), 7.55-7.80 (1H, m), 7.96 (1H, d, J = 8.7 Hz), 8.34 (1H, brs), 10.15(2H, brs) Dihydro- chloride 187 —CH₃

1H-NMR (CDCl3) δ ppm: 1.23-1.76 (5H, m), 1.75 (3H, s), 1.84-2.21 (2H,m), 2.14 (3H, s), 2.24-2.44 (2H, m), 2.66 (3H, d, J = 4.9 Hz), 3.49 (1H,d, J = 13.6 Hz), 4.06-4.20 (1H, m), 4.65 (1H, d, J = 13.6 Hz), 4.90-5.01(1H, m), 7.48 (1H, d, J = 5.5 Hz), 7.65 (1H, d, J = 5.0 Hz), 7.74-9.30(2H, br), 7.97-8.10 (1H, m), 18.12 (1H, brs) Dihydro- chloride 188 —H

1H-NMR (CDCl3) δ ppm: 1.26-2.06 (8H, m), 1.75 (3H, s), 2.05 (3H, s),2.46-2.52 (1H, m), 3.23 (1H, d, J = 13.4 Hz), 3.70-4.05 (2H, br), 3.66(1H, d, J = 13.4 Hz), 7.36 (1H, d, J = 5.5 Hz), 7.56 (1H, d, J = 6.6Hz), 7.87 (1H, brs), 7.89 (1H, d, J = 8.6 Hz), 8.38 (1H, brs), 10.03(2H, brs) Dihydro- chloride 189 —CH₃

1H-NMR (CDCl3) δ ppm: 1.18-1.35 (1H, m), 1.39-1.53 (1H, m), 1.55-1.75(2H, m), 1.74 (3H, s), 1.64-1.96 (1H, m), 2.02-2.39 (4H, m), 2.08 (3H,s), 2.84 (3H, d, J = 4.9 Hz), 3.42 (1H, d, J = 13.5 Hz), 3.96-4.07 (1H,m), 4.56 (1H, d, J = 13.5 Hz), 4.78-4.84 (1H, m), 7.39 (1H, d, J = 5.5Hz), 7.63 (1H, d, J = 5.5 Hz), 7.90-7.99 (2H, m), 8.780 (1H, br), 13.05(1H, brs) Dihydro- chloride 190 —H

1H-NMR (DMSO-d6) δ ppm: 0.90-1.48 (6H, m), 1.48-1.80 (7H, m), 1.90-2.07(1H, m), 2.87-3.16 (3H, m), 3.16-3.32 (1H, m), 7.23 (1H, d, J = 7.5 Hz),7.40-7.52 (2H, m), 7.67-7.79 (2H, m), 8.92-9.22 (1H, br), 9.40-9.70 (1H,br). Hydro- chloride

TABLE 29 Absolute configuration

Ex- am- ple R¹ R⁴ NMR Salt 191 —H

1H-NMR (DMSO-d6) δ ppm: 0.95-1.46 (6H, m), 1.46-1.85 (7H, m), 1.95-2.12(1H, m), 2.80-3.40 (4H, m), 5.50-8.80 (1H, br), 6.75-7.20 (2H, m),7.20-7.37 (1H, m), 7.37-1.83 (1H, m), 7.99 (1H, s), 9.00-9.50 (1H, br),9.60-10.05 (1H, br). Dihydro- chloride 192 —H

1H-NMR (DMSO-d6) δ ppm at 80° C.: 0.96-1.28 (2H, m), 1.26-1.51 (5H, m),1.51-1.61 (1H, m), 1.61-1.78 (5H, m), 1.99-2.08 (1H, m), 2.80 (1H, d, J= 12.3 Hz), 3.05-3.32 (3H, m), 3.56-4.12 (1H, br), 7.01 (1H, dd, J =3.6, 8.5 Hz), 7.08-7.13 (2H, m), 8.01 (1H, d, J = 2.1 Hz), 9.10-9.35(1H, br), 9.38-9.75 (1H, br). Dihydro- chloride 193 —H

1H-NMR (DMSO-d6) δ ppm at 80° C.: 0.98-1.27 (2H, m), 1.27-1.46 (4H, m),1.48-1.80 (2H, m), 1.60-1.80 (6H, m), 1.98-2.10 (1H, m), 2.84 (1H, d, J= 12.4 Hz), 3.05-3.35 (3H, m), 3.45-3.90 (1H, br), 7.08 (1H, d, J = 8.2Hz), 7.08-7.18 (1H, br), 7.38 (1H, d, J = 8.2 Hz), 8.03 (1H, d, J = 2.2Hz), 8.98-9.35 (1H, br), 9.35-9.72 (1H, br). Dihydro- chloride 194 —H

1H-NMR (CDCl3) δ ppm: 0.82-1.05 (2H, m), 1.07 (3H, s), 1.19-1.43 (3H,m), 1.49 (3H, s), 1.56-1.88 (1H, m), 1.68-1.90 (3H, m), 2.35-2.51 (4H,m), 2.51-2.70 (1H, m), 2.76-2.92 (2H, m), 6.83-6.89 (2H, m), 7.01 (1H,d, J = 7.8 Hz), 7.56 (1H, d, J = 2.1 Hz). — 195 —H

1H-NMR (DMSO-d6) δ ppm at 80° C.: 0.96-1.25 (2H, m), 1.25-1.80 (6H, m),1.60-1.79 (5H, m), 1.98-2.10 (1H, m), 2.76 (1H, d, J = 12.3 Hz),2.99-3.37 (3H, m), 3.93 (3H, s), 4.62-4.66 (1H, br), 6.68 (1H, d, J =8.4 Hz), 6.95 (1H, d = 8.4 Hz), 8.96-7.09 (1H, br), 7.87 (1H, d, J = 2.1Hz), 9.02-9.40 (1H, br), 9.40-9.75 (1H, br). Dihydro- chloride 196 —H

1H-NMR (CDCl3) δ ppm: 1.18-1.36 (1H, m), 1.41-1.63 (2H, m), 1.73-2.10(5H, m), 1.75 (3H, s), 2.17 (3H, s), 2.36-2.69 (1H, m), 3.36 (1H, d, J =12.8 Hz), 3.52-4.40 (2H, br), 4.09 (1H, d, J = 12.8 Hz), 6.88 (1H, d, J= 2.0 Hz), 7.62 (1H, d, J = 8.7 Hz), 7.74 (1H, d, J = 2.0 Hz), 7.70-8.76(2H, br), 9.50-10.65 (2H, br) Dihydro- chloride 197 —H

1H-NMR (DMSO-d6) δ ppm at 80° C.: 1.03-1.44 (6H, m), 1.51-1.79 (7H, m),2.00-2.10 (1H, m), 2.87 (1H, d, J = 12.4 Hz), 2.9-3.05 (1H, m),3.10-3.23 (2H, m), 4.64-5.12 (1H, br), 6.88 (1H, d, J = 1.4 Hz),7.05-7.09 (1H, m), 7.33-7.38 (1H, br), 7.59 (1H, d, J = 8.2 Hz), 7.89(1H, J = 2.2 Hz), 8.97-9.28 (1H, br), 9.45-9.62 (1H, br). Dihydro-chloride

TABLE 30 Absolute configuration

Ex- am- ple R¹ R⁴ NMR Salt 198 —H

1H-NMR (CDCl3) δ ppm: 0.93-1.80 (35H, m), 1.80-2.05 (1H, br), 2.40-2.70(2H, m), 2.81-2.95 (1H, m), 3.00-3.15 (1H, m), 6.72 (1H, d, J = 2.7 Hz),6.80 (1H, d, J = 7.4 Hz), 7.00-7.13 (1H, m), 7.17 (1H, d, J = 3.2 Hz),7.23-7.34 (1H, m). — 199 —H

1H-NMR (CDCl3) δ ppm: 0.99-1.50 (5H, m), 1.07 (3H, s), 1.13 (9H, s),1.15 (9H, s), 1.42 (3H, s), 1.58-1.73 (7H, m), 2.23-2.31 (1H, m), 2.88(1H, d, J = 11.2 Hz), 2.73- 2.79 (1H, m), 2.63 (1H, d, J = 11.2 Hz),8.55 (1H, dd, J = 3.2, 0.7 Hz), 6.92 (1H, dd, J = 8.8, 2.1 Hz), 7.21(1H, d, J = 3.2 Hz), 7.34 (1H, d, J = 2.1 Hz), 7.37 (1H, d, J = 8.8 Hz)— 200 —H

1H-NMR (CDCl3) δ ppm: 0.85-1.85 (36H, m), 2.25-2.89 (1H, m), 2.60 (1H,d, J = 11.2 Hz), 2.76-2.90 (2H, m), 6.54-6.60 (1H, m), 6.90 (1H, dd, J =1.7, 8.3 Hz), 7.17-7.32 (2H, m), 7.50 (1H, d, J = 8.3 Hz). — 201 —H

1H-NMR (CDCl3) δ ppm: 1.01-1.44 (5H, m), 1.08 (3H, s), 1.13 (9H, s),1.15 (9H, s), 1.42 (3H, s), 1.56-1.83 (7H, m), 2.25-2.33 (1H, m), 2.67(1H, d, J = 11.3 Hz), 2.77-2.83 (1H, m), 2.82 (1H, d, J = 11.3 Hz), 7.13(1H, dd, J = 8.9, 2.0 Hz), 7.43 (1H, d, J = 2.0 Hz), 7.45 (1H, d, J =8.9 Hz), 5.15 (1H, d, J = 0.8 Hz) —

TABLE 31 Absolute configuration

Ex- Melting am- point ple R¹ R⁴ NMR (° C.) Salt 202 —H

1H-NMR (CDCl3) δ ppm: 0.80-1.18 (5H, m), 1.18-1.46 (3H, m), 1.46-1.66(4H, m), 1.88-2.05 (3H, m), 2.40-2.70 (2H, m), 2.80-2.98 (1H, m), 3.03(1H, d, J = 11.3 Hz), 8.64-8.72 (1H, m), 8.83 (1H, dd, J = 1.6, 6.6 Hz),7.07-7.20 (3H, m), 6.16-6.35 (1H, br). — 203 —H

1H-NMR (CDCl3) δ ppm: 0.95-1.08 (1H, m), 1.07 (3H, s), 1.13-1.37 (4H,m), 1.43 (3H, s), 1.55-1.73 (4H, m), 2.25-2.33 (1H, m), 2.68 (1H, d, J =11.1 Hz), 2.75-2.83 (1H, m), 2.81 (1H, d, J = 11.1 Hz), 6.48-6.50 (1H,m), 7.01 (1H, dd, J = 8.6, 1.9 Hz), 7.17-7.20 (1H, m), 7.30 (1H, d, J =8.6 Hz), 7.38 (1H, d, J = 1.9 Hz), 6.11 (1H, brs) — 204 —CH₂

1H-NMR (CDCl3) δ ppm: 1.01-1.30 (3H, m), 1.09 (3H, s), 1.22 (3H, s),1.50-1.76 (4H, m), 1.99-2.15 (1H, m), 2.25 (3H, s), 2.27-2.36 (1H, m),2.54-2.64 (1H, m), 2.70 (1H, d, J = 11.2 Hz), 2.91 (1H, d, J = 11.2 Hz),6.46-6.50 (1H, m), 7.02 (1H, dd, J = 6.6, 1.5 Hz), 7.17-7.20 (1H, m),7.31 (1H, d, J = 6.6 Hz), 7.39 (1H, s), 8.10 (1H, brs) — 205 —H

1H-NMR (CDCl3) δ ppm: 0.50-1.40 (6H, m), 1.43 (3H, s), 1.55-1.88 (4H,m), 2.27-2.40 (1H, m), 2.68 (1H, d, J = 11.3 Hz), 2.75-2.91 (2H, m),6.46-6.56 (1H, m), 6.94 (1H, dd, J = 1.8, 8.4 Hz), 7.13-7.22 (2H, m),7.53 (1H, d, J = 8.4 Hz), 8.15-8.48 (1H, br). — 206 —H

1H-NMR (MeOH-d4) δ ppm: 0.87-1.95 (14H, m), 2.66-3.02 (3H, m), 3.09-3.30(3H, m), 3.69 (3H, s), 6.43 (1H, s), 6.58 (1H, s), 6.77 (1H, d, J = 7.6Hz), 6.93-7.20 (3H, m). Hami- fumarate 207 —CH₃

1H-NMR (DMSO-d6) δ ppm: 0.65-1.55 (11H, m), 1.83-1.85 (2H, m), 2.05-2.20(1H, m), 2.41 (3H, brs), 2.60-3.00 (4H, m), 3.00-4.80 (6H, m), 6.36-6.52(1H, br), 6.56 (2H, s), 6.79 (1H, d, J = 7.5 Hz), 7.03-7.15 (1H, m),7.15-7.30 (2H, m). Fumarate 208 —CH₃

1H-NMR (DMSO-d6) δ ppm: 0.89-1.40 (10H, m), 10.40-10.58 (2H, m),10.63-10.80 (1H, m), 2.01-2.27 (1H, m), 2.39 (3H, s), 2.66-2.78 (3H, m),2.92-3.08 (1H, m), 4.65 (5H, m), 6.35 (1H, d, J = 2.6 Hz), 8.55 (2H, s),6.90-7.00 (1H, m), 7.24-7.32 (2H, m), 7.34 (1H, d, J = 5.6 Hz). Fumarate209 —H

1H-NMR (DMSO-d6) δ ppm: 0.90-1.63 (12H, m), 1.63-1.77 (1H, m), 1.82-1.99(1H, m), 2.80-2.88 (2H, m), 2.91-3.14 (2H, m), 3.75 (3H, s), 3.80-5.30(2H, br), 6.38 (1H, d, J = 3.0 Hz), 6.46 (2H, s), 6.85 (1H, d, J = 8.4Hz), 7.14 (1H, s), 7.27 (1H, d, J = 3.0 Hz), 7.48 (1H, d, J = 8.4 Hz),8.76-10.00 (1H, br). Fumarate 210 —CH₃

1H-NMR (DMSO-d6) δ ppm: 0.90-1.35 (10H, m), 1.40-1.55 (2H, m), 1.55-1.80(1H, m), 2.02-2.16 (1H, m), 2.39 (3H, s), 2.55-2.80 (3H, m), 2.90-3.08(1H, m), 3.16-4.70 (5H, m), 6.32-6.40 (1H, m), 6.56 (2H, s), 6.65 (1H,dd, J = 1.5, 8.4 Hz), 7.14 (1H, s), 7.26 (1H, d, J = 3.1 Hz), 7.45 (1H,d, J = 8.4 Hz). Fumarate 211 —H

209.8- 214.2 Fumarate 212 —H

1H-NMR (CDCl3) δ ppm: 0.96-1.15 (1H, m), 1.09 (3H, s), 1.19-1.39 (4H,m), 1.44 (3H, s), 1.52-1.82 (2H, m), 1.69-1.82 (2H, m), 2.27-2.35 (1H,m), 2.68 (1H, d, J = 11.1 Hz), 2.75-2.85 (1H, m), 2.51 (1H, d, J = 11.1Hz), 7.22 (1H, dd, J = 6.8, 1.9 Hz), 7.37-7.45 (2H, m), 6.01 (1H, s),9.54-10.50 (1H, br) — 213 —CH₃

1H-NMR (CDCl3) δ ppm: 0.99-1.30 (4H, m), 1.10 (3H, s), 1.22 (3H, s),1.41-1.67 (2H, br), 1.70-1.80 (1H, m), 1.88-2.18 (1H, m), 2.26 (3H, s),2.20-2.37 (1H, m), 2.57-2.84 (1H, m), 2.69 (1H, d, J = 11.1 Hz), 2.88(1H, d, J = 11.1 Hz), 5.85 (1H, s), 7.21-7.28 (1H, m), 7.40-7.53 (2H,m), 6.01 (1H, s) — 214 —H

1H-NMR (DMSO-d6) δ ppm: 1.00-1.51 (7H, m), 1.51-1.85 (6H, m), 1.92-2.20(1H, brs), 2.60-3.70 (4H, m), 4.04 (3H, s), 6.85-7.90 (3H, m), 7.90-8.18(1H, brs), 8.75-10.40 (3H, brm). Dihydro- chloride 215 —H

1H-NMR (DMSO-d6) δ ppm: 0.95-1.40 (5H, m), 1.40-1.65 (6H, m), 1.65-1.80(1H, m), 1.65-2.00 (1H, m), 2.65-2.80 (2H, m), 2.65-3.00 (1H, m),3.00-3.21 (1H, m), 3.98-4.55 (1H, br), 8.00 (2H, s), 6.55-6.65 (1H, m),6.73 (1H, d, J = 1.6 Hz), 6.88 (1H, d, J = 8.2 Hz), 8.66-8.95 (1H, br),9.22-9.52 (1H, br). Dihydro- chloride 216 —H

1H-NMR (DMSO-d6) δ ppm: 1.04-1.48 (4H, m), 1.35 (3H, s), 1.50-1.75 (4H,m), 1.89 (3H, s), 1.94-1.99 (1H, m), 2.82-2.92 (1H, m), 2.97 (1H, d, J =12.3 Hz), 3.07 (1H, d, J = 12.3 Hz), 3.13-3.28 (1H, m), 7.28 (1H, dd, J= 8.5, 1.8 Hz), 7.51 (1H, d, J = 1.6 Hz), 8.12 (1H, d, J = 6.5 Hz),8.55-9.05 (1H, br), 9.41 (1H, s), 9.46-9.58 (1H, br) Dihydro- chloride

TABLE 32 Absolute configuration

Ex- Melting am- point ple R¹ R⁴ NMR (° C.) Salt 217 —H

1H-NMR (DMSO-d6) δ ppm: 1.00-1.44 (6H, m), 1.50-1.79 (7H, m), 1.96-2.06(1H, m), 2.82-3.00 (2H, m), 3.00-3.25 (2H, m), 3.61 (3H, s), 6.82 (1H,d, J = 9.5 Hz), 7.38-7.46 (1H, m), 7.48-7.58 (2H, m), 7.91 (1H, d, J =9.5 Hz), 7.98-8.52 (1H, br), 9.14-9.37 (1H, br), 9.55-9.66 (1H, br).Dihydrochloride 218 —H

1H-NMR (CDCl3) δ ppm: 0.87-1.03 (1H, m), 1.09 (3H, m), 1.15-1.46 (4H,m), 1.46-1.65 (5H, m), 1.65-1.88 (2H, m), 2.47-2.60 (1H, m), 2.65 (1H,d, J = 11.3 Hz), 2.76 (1H, d, J = 11.3 Hz), 2.90-3.04 (1H, m), 7.25 (1H,d, J = 7.3 Hz), 7.40 (1H, dd, J = 4.2, 8.5 Hz), 7.65-7.72 (1H, m), 7.91(1H, d, J = 8.5 Hz), 8.85 (1H, d, J = 8.5 Hz), 8.90 (1H, dd, J = 1.7,4.2 Hz). — 219 —H

1H-NMR (CDCl3) δ ppm: 0.93-1.12 (5H, m), 1.22-1.46 (3H, m), 1.55-1.70(4H, m), 1.73-1.90 (3H, m), 2.50 (1H, d, J = 11.5 Hz), 2.55-2.65 (1H,m), 2.92-3.05 (2H, m), 7.09 (1H, d, J = 4.8 Hz), 7.49-7.58 (1H, m),7.65-7.72 (1H, m), 8.05-8.10 (1H, m), 8.36 (1H, dd, J = 1.0, 8.4 Hz),8.84 (1H, d, J = 4.6 Hz). — 220 —H

1H-NMR (CDCl3) δ ppm: 0.80-1.17 (5H, m), 1.21-1.50 (8H, m), 1.61-1.66(4H, m), 2.42-2.50 (1H, m), 2.74 (1H, d, J = 11.4 Hz), 2.80-2.90 (1H,m), 2.96 (1H, d, J = 11.4 Hz), 7.31-7.39 (2H, m), 7.50 (1H, dd, J = 2.4,9.0 Hz), 8.01 (1H, d, J = 9.0 Hz), 6.06 (1H, dd, J = 1.1, 8.3 Hz), 8.81(1H, dd, J = 1.7, 4.2 Hz). — 221 —H

1H-NMR (CDCl3) δ ppm: 1.04-1.20 (4H, m), 1.20-1.48 (7H, m), 1.67-1.86(3H, m), 1.96 (1H, dd, J = 3.0, 13.0), 2.61-2.70 (1H, m), 2.62-2.95 (2H,m), 3.07 (1H, d, J = 12.0 Hz), 7.20 (1H, d, J = 1.8 Hz), 7.32 (1H, dd, J= 2.1, 8.8 Hz), 7.50 (1H, d, J = 5.8 Hz), 7.84 (1H, d, J = 8.8 Hz), 8.41(1H, d, J = 5.6 Hz), 9.09 (1H, s). —

TABLE 33 Absolute configuration

Ex- am- ple R¹ R⁵ R⁶ R⁷ R⁸ R⁹ NMR Salt 222 —H —H —H —F —H —H 1H-NMR(CDCl3) δ ppm: 1.21-1.36 (1H, m), 1.44-1.61 (2H, m), 1.88-2.00Dihydrochloride (3H, m), 1.78 (3H, s), 2.09-2.30 (1H, m), 2.22 (3H, s),2.51-2.55 (1H, m), 3.42 (1H, d, J = 13.2 Hz), 3.92-4.12 (1H, m), 4.15(1H, d, J = 13.2 Hz), 4.37-4.44 (1H, m), 7.22-7.27 (4H, m), 7.90-8.48(1H, br), 9.90-10.18 (1H, m), 10.32-10.60 (1H, brs) 223 —CH₃ —H —H —F —H—H 1H-NMR (CDCl3) δ ppm: 0.90-1.10 (1H, m), 1.14-1.36 (2H, m), 1.40-1.75Dihydrochloride (2H, m), 1.53 (3H, s), 1.59 (3H, s), 1.55-1.95 (1H, m),2.01-2.23 (2H, m), 2.72 (3H, d, J = 5.0 Hz), 2.75 (1H, d, J = 12.9 Hz),2.87-3.08 (1H, m), 3.40-3.50 (1H, m), 3.60 (1H, d, J = 12.9 Hz),6.96-7.04 (2H, m), 7.16-7.23 (2H, m), 12.10 (1H, brs) 224 —H —H —F —F —H—H 1H-NMR (CDCl3) δ ppm: 1.17-1.48 (3H, m), 1.53-1.74 (2H, m), 1.66 (3H,Hydrochlroide s), 1.79 (3H, s), 1.79 (1H, brs), 1.88-2.05 (1H, m),2.24-2.48 (1H, m), 2.88 (1H, d, J = 12.5 Hz), 3.10-3.40 (2H, m), 3.43(1H, d, J = 12.5 Hz), 7.13-7.16 (2H, m), 7.20-7.28 (1H, m), 9.40-9.75(1H, br), 9.76-10.08 (1H, br) 225 —CH₃ —H —F —F —H —H 1H-NMR (CDCl3) δppm: 1.19-1.41 (3H, m), 1.61 (8H, brs), 1.80-2.02 (1H, Hydrochloride m),2.04-2.24 (2H, m), 2.74 (3H, d, J = 5.0 Hz), 2.87 (1H, d, J = 12.8 Hz),3.08-3.20 (1H, m), 3.62-3.78 (1H, m), 3.92 (1H, d, J = 12.8 Hz),7.11-7.19 (2H, m), 7.27-7.32 (1H, m), 12.08 (1H, brs) 226 —H —H —Cl —F—H —H 1H-NMR (CDCl3) δ ppm: 1.13-1.42 (3H, m), 1.47-1.81 (3H, m), 1.65(3H, Hydrochloride s), 1.74 (3H, s), 1.86-2.05 (1H, m), 2.32-2.38 (1H,m), 2.80 (1H, d, J = 12.5 Hz), 3.07-3.16 (1H, m), 3.19-3.29 (1H, m),3.36 (1H, d, J = 12.5 Hz), 7.07-7.21 (2H, m), 7.34 (1H, dd, J = 6.5, 2.3Hz), 9.56 (1H, brs), 9.82-9.88 (1H, br) 227 —H —H —CH₃ —F —H —H 1H-NMR(DMSO-d6) δ ppm: 1.00-1.45 (6H, m), 1.45-1.81 (7H, m), Dihydrochloride1.81-2.10 (1H, m), 2.22 (3H, d, J = 1.5 Hz), 2.78-3.00 (2H, m),3.00-3.27 (2H, m), 4.10-4.98 (1H, br), 6.96-7.23 (3H, m), 9.00-9.40 (1H,br), 9.56-9.92 (1H, br). 228 —H —H —OCH₃ —F —H —H 1H-NMR (DMSO-d6) δ ppmat 80° C.: 1.00-1.43 (6H, m), 1.49-1.77 (7H, Dihydrochloride m),1.97-2.08 (1H, m), 2.81 (1H, d, J = 12.3 Hz), 2.84-2.93 (1H, m),3.04-3.18 (2H, m), 3.83 (3H, s), 4.30-4.57 (1H, br), 6.66-6.74 (1H, m),8.86 (1H, dd, J = 2.5, 7.9 Hz), 7.11 (1H, dd, J = 6.6, 11.4 Hz),8.94-9.25 (1H, br), 9.49-9.80 (1H, br). 229 —H —H —F —CH₃ —H —H 1H-NMR(CDCl3) δ ppm: 1.21-1.51 (2H, m), 1.82-1.97 (5H, m), 1.72 (3H,Hydrochloride s), 2.03 (3H, s), 2.29 (3H, s), 2.44-2.49 (1H, m), 3.21(1H, d, J = 12.9 Hz), 3.66-3.87 (2H, m), 3.21 (1H, d, J = 12.9 Hz),7.25-7.31 (1H, m), 7.47-7.82 (2H, m), 10.00 (2H, brs) 230 —CH₃ —H —F—CH₃ —H —H 1H-NMR (CDCl3) δ ppm: 1.20-1.40 (3H, m), 1.48-1.75 (2H, m),1.61 (3H, Hydrochloride s), 1.64 (3H, s), 1.84-1.93 (1H, m), 2.11-2.16(2H, m), 2.26 (3H, d, J = 1.9 Hz), 2.73 (3H, d, J = 5.0 Hz), 2.90 (1H,d, J = 12.9 Hz), 3.12-3.24 (1H, m), 3.65-3.80 (1H, m), 3.92 (1H, d, J =12.9 Hz), 7.09-7.21 (3H, m), 12.33 (1H, brs) 231 —H —H —F —Cl —H —H1H-NMR (CDCl3) δ ppm: 1.01-1.12 (1H, m), 1.20-1.39 (2H, m), 1.56-2.04Hydrochloride (4H, m), 1.53 (3H, s), 1.69 (3H, s), 2.31-2.36 (1H, m),2.78 (1H, d, J = 12.4 Hz), 2.97-3.04 (1H, m), 3.13-3.24 (1H, m), 3.29(1H, d, J = 12.4 Hz), 6.91-7.01 (2H, m), 7.34 (1H, dd, J = 8.4, 8.3 Hz),9.60 (1H, brs), 9.80 (1H, brs) 232 —CH₃ —H —F —Cl —H —H 1H-NMR (CDCl3) δppm: 1.00-1.18 (1H, m), 1.17-1.40 (2H, m), 1.58 (3H, Hydrochloride s),1.60 (3H, s), 1.60-1.81 (3H, m), 1.90-1.94 (1H, m), 2.04-2.25 (1H, m),2.72 (3H, d, J = 4.9 Hz), 2.78 (1H, d, J = 12.8 Hz), 2.92-3.04 (1H, m),3.46-3.55 (1H, m), 3.61 (1H, d, J = 12.8 Hz), 7.00-7.08 (2H, m),7.32-7.39 (1H, m), 12.26 (1H, brs) 233 —H —H —F —OCH₃ —F —H 1H-NMR(DMSO-d6) δ ppm: 1.02-1.34 (3H, m), 1.33 (3H, s), 1.51 (3H, s),Dihydrochloride 1.54-1.73 (4H, m), 1.96-2.01 (1H, m), 2.76-2.83 (1H, m),2.89 (1H, d, J = 12.5 Hz), 2.98 (1H, d, J = 12.5 Hz), 3.08-3.18 (1H, m),3.67 (3H, s), 4.76 (1H, s), 6.88-8.98 (2H, m), 9.01-9.09 (1H, m),9.70-9.75 (1H, m) 234 —H —H —F —OCH₃ —H —H 1H-NMR (DMSO-d6) δ ppm:1.05-1.48 (6H, m), 1.45-1.80 (7H, m), Dihydrochloride 1.95-2.08 (1H, m),2.70-2.90 (2H, m), 2.95-3.23 (2H, m), 3.81 (3H, s), 4.85-5.40 (1H, br),6.66-7.06 (2H, m), 7.08-7.22 (1H, m), 8.90-9.25 (1H, br), 9.65-9.85 (1H,br). 235 —H —H —Cl —H —H —H 1H-NMR (CDCl3) δ ppm: 1.05-1.13 (1H, m),1.23-1.35 (2H, m), 1.50-1.78 Hydrochloride (3H, m), 1.63 (3H, s), 1.71(3H, s), 1.92-2.08 (1H, m), 2.31-2.36 (1H, m), 2.78 (1H, d, J = 12.7Hz), 3.00-3.09 (1H, m), 3.15-3.26 (1H, m), 3.31 (1H, d, J = 12.7 Hz),7.07-7.10 (1H, m), 7.15-7.19 (2H, m), 7.23-7.29 (1H, m), 9.50 (1H, brs),9.79 (1H, brs) 236 —CH₃ —H —Cl —H —H —H 1H-NMR (CDCl3) δ ppm: 1.18-1.50(2H, m), 1.60-1.81 (2H, m), 1.71 (3H, Dihydrochloride s), 1.91-2.30 (6H,m), 2.00 (3H, s), 2.80 (3H, d, J = 4.9 Hz), 3.32 (1H, d, J = 13.4 Hz),3.81-3.94 (1H, m), 4.42 (1H, d, J = 13.4 Hz), 4.61-4.70 (1H, m),7.42-7.50 (2H, m), 7.97 (1H, brs), 8.13 (1H, brs), 13.7 (1H, brs) 237 —H—H —Cl —CN —H —H 1H-NMR (CDCl3) δ ppm: 1.05-1.20 (1H, m), 1.23-1.44 (2H,m), 1.54-2.10 Hydrochloride (4H, m), 1.63 (3H, s), 1.88 (3H, s),2.35-2.40 (1H, m), 2.89 (1H, d, J = 12.7 Hz), 3.19 (2H, br), 3.34 (1H,d, J = 12.7 Hz), 7.08 (1H, dd, J = 8.4, 2.0 Hz), 7.20 (1H, d, J = 2.0Hz), 7.61 (1H, d, J = 8.4 Hz), 9.62 (1H, brs), 9.90 (1H, br) 238 —CH₃ —H—Cl —CN —H —H 1H-NMR (CDCl3) δ ppm: 1.01-1.15 (1H, m), 1.23-1.46 (2H,m), 1.50 (3H, Hydrochloride s), 1.61 (3H, s), 1.81-1.98 (3H, m),2.09-2.27 (2H, m), 2.72 (8H, d, J = 4.9 Hz), 2.67 (1H, d, J = 13.0 Hz),2.91-3.03 (1H, m), 3.63-3.72 (1H, m), 3.84 (1H, d, J = 13.0 Hz), 7.14(1H, dd, J = 6.4, 2.1 Hz), 7.26 (1H, d, J = 2.1 Hz), 7.62 (1H, d, J =8.4 Hz), 12.38 (1H, brs) 239 —H —H —Cl —CH₃ —H —H 1H-NMR (CDCl3) δ ppm:1.25-2.04 (7H, m), 1.75 (3H, s), 2.13 (3H, s), Hydrochloride 2.40 (3H,s), 2.48-2.53 (1H, m), 3.33 (1H, d, J = 13.1 Hz), 3.88-3.92 (1H, m),3.97 (1H, d, J = 13.1 Hz), 4.10-4.17 (1H, m), 7.38 (1H, d, J = 8.4 Hz),7.78 (1H, d, J = 8.4 Hz), 8.00 (1H, s), 10.03-10.07 (1H, m), 10.20-10.30(1H, m) 240 —CH₃ —H —Cl —CH₃ —H —H 1H-NMR (CDCl3) δ ppm: 1.14-1.41 (3H,m), 1.47-1.74 (2H, m), 1.56 (3H, Hydrochloride s), 1.80 (3H, s),1.89-1.93 (1H, m), 2.10-2.22 (2H, m), 2.35 (3H, s), 2.72 (3H, d, J = 4.9Hz), 2.83 (1H, d, J = 12.9 Hz), 3.00-3.15 (1H, m), 3.45-3.67 (1H, m),3.65 (1H, d, J = 12.8 Hz), 7.11-7.22 (2H, m), 7.32 (1H, s), 12.24 (1H,brs) 241 —H —H —Cl —OCH₃ —H —H 1H-NMR (DMSO-d6) δ ppm: 0.95-1.41 (6H,m), 1.41-1.80 (7H, m), Dihydrochloride 1.88-2.05 (1H, m), 2.69-2.90 (2H,m), 2.93-3.05 (1H, m), 3.05 (1H, m), 3.05-3.24 (1H, m), 3.83 (3H, s),4.15-5.35 (1H, br), 7.02-7.25 (3H, m), 8.87-9.16 (1H, br), 9.40-9.72(1H, br). 242 —H —H —H —Cl —H —H 1H-NMR (CDCl3) δ ppm: 1.13-1.24 (1H,m), 1.25-1.36 (2H, m), 1.80-1.83 Hydrochloride (3H, m), 1.64 (3H, s),1.74 (3H, s), 1.89-2.02 (1H, m), 2.32-2.37 (1H, m), 2.80 (1H, d, J =12.5 Hz), 3.12-3.18 (1H, m), 3.22-3.29 (1H, m), 3.36 (1H, d, J = 12.5Hz), 7.19-7.22 (2H, m), 7.29-7.33 (2H, m), 9.52 (1H, brs), 9.81 (1H,brs) 243 —CH₃ —H —H —Cl —H —H 1H-NMR (CDCl3) δ ppm: 1.02-1.40 (3H, m),1.48-1.75 (2H, m), 1.81 (3H, Hydrochloride s), 1.63 (3H, s), 1.80-2.02(1H, m), 2.11-2.18 (2H, m), 2.74 (3H, d, J = 5.0 Hz), 2.88 (1H, d, J =12.9 Hz), 3.10-3.22 (1H, m), 3.66-3.76 (1H, m), 3.93 (1H, d, J = 12.9Hz), 7.30-7.38 (4H, m), 12.28 (1H, brs) 244 —H —H —CH₃ —Cl —H —H 1H-NMR(DMSO-d6) δ ppm: 0.90-1.79 (13H, m), 1.79-1.95 (1H, m), 2.29 Fumarate(3H, s), 2.58-3.08 (4H, m), 3.10-4.90 (3H, br), 6.48 (2H, s), 6.89-7.00(1H, m), 7.07 (1H, d, J = 2.3 Hz), 7.33 (1H, d, J = 8.5 Hz). 245 —H —H—OCH₃ —Cl —H —H 1H-NMR (DMSO-d6) δ ppm: 1.00-1.45 (6H, m), 1.45-1.82(7H, m), Dihydrochloride 1.95-2.10 (1H, m), 2.78-3.10 (3H, m), 3.10-3.27(1H, m), 3.85 (3H, s), 4.00-4.65 (1H, br), 6.73 (1H, dd, J = 2.1, 8.4Hz), 6.80 (1H, d, J = 2.1 Hz), 7.37 (1H, d, J = 8.4 Hz), 8.90-9.18 (1H,br), 9.61-9.85 (1H, br). 246 —H —H —Cl —Cl —H —H 1H-NMR (CDCl3) δ ppm:1.16-1.45 (3H, m), 1.58-1.61 (3H, m), 1.65 (3H, Hydrochloride s), 1.75(3H, s), 1.88-2.04 (1H, m), 2.32-2.38 (1H, m), 2.62 (1H, d, J = 12.6Hz), 3.12-3.31 (2H, m), 3.38 (1H, d, J = 12.8 Hz), 7.15 (1H, dd, J =8.5, 2.3 Hz), 7.40 (1H, d, J = 2.3 Hz), 7.42 (1H, d, J = 8.5 Hz), 9.57(1H, br), 9.82 (1H, br) 247 —CH₃ —H —Cl —Cl —H —H 1H-NMR (CDCl3) δ ppm:1.23-1.49 (2H, m), 1.60-1.75 (2H, m), 1.69 (3H, Hydrochloride s), 1.91(3H, s), 1.91-2.15 (3H, m), 2.22-2.26 (1H, m), 2.79 (3H, d, J = 4.9 Hz),3.23 (1H, d, J = 13.2 Hz), 3.64-3.76 (1H, m), 4.38 (1H, d, J = 13.2 Hz),4.43-4.62 (1H, m), 7.56 (1H, d, J = 8.7 Hz), 7.82 (1H, dd, J = 8.7, 2.3Hz), 8.14 (1H, d, J = 2.3 Hz), 12.88 (1H, brs) 248 —H —H —H —OCH₃ —H —H1H-NMR (DMSO-d6) δ ppm: 1.02-1.50 (7H, m), 1.50-1.62 (6H, m),Dihydrochloride 1.96-2.18 (1H, m), 2.80-3.60 (4H, m), 3.76 (3H, s),6.65-7.10 (2H, m), 7.10-7.68 (2H, m), 8.80-10.90 (3H, m). 249 —H —H—OCH₃ —F —H —H 1H-NMR (DMSO-d6) δ ppm at 80° C.: 1.00-1.43 (6H, m),1.49-1.77 (7H, Dihydrochloride m), 1.97-2.06 (1H, m), 2.81 (1H, d, J =12.3 Hz), 2.84-2.94 (1H, m), 3.04-3.16 (2H, m), 3.63 (3H, s), 4.30-4.57(1H, br), 6.68-6.74 (1H, m), 6.86 (1H, dd, J = 2.5, 7.9 Hz), 7.11 (1H,dd, J = 8.6, 11.4 Hz), 8.94-9.25 (1H, br), 9.49-9.60 (1H, br).

TABLE 34 Absolute configuration

Ex- am- ple R¹ R⁴ NMR Salt 250 —H

1H-NMR (CDCl3) δ ppm: 1.10-1.47 (3H, m), 1.46-2.16 (4H, m), 1.69 (3H,s), 1.78 (3H, s), 2.30-2.54 (1H, m), 2.95 (1H, d, J = 12.5 Hz),3.20-3.50 (2H, br), 3.52 (1H, d, J = 12.5 Hz), 7.37-7.52 (2H, m),7.60-8.00 (4H, m), 9.18-10.05 (2H, br) Hydro- chloride 251 —CH₃

1H-NMR (CDCl3) δ ppm: 1.20-1.35 (1H, m), 1.41-1.55 (1H, m), 1.59-1.82(2H, m), 1.75 (3H, s), 1.91-2.01 (1H, m), 2.02-2.15 (2H, m), 2.14 (3H,s), 2.30-2.44 (2H, m), 2.85 (3H, d, J = 4.8 Hz), 3.49 (1H, d, J = 13.5Hz), 4.07-4.19 (1H, m), 4.66 (1H, d, J = 13.5 Hz), 4.92-5.01 (1H, m),7.59-7.66 (2H, m), 7.88-8.04 (4H, m), 8.87 (1H, br), 13.11 (1H, brs)Dihydro- chloride 252 —H

1H-NMR (DMSO-d6) δ ppm: 0.94-1.25 (2H, m), 1.25-1.45 (5H, m), 1.45-1.55(1H, m), 1.55-1.80 (6H, m), 1.95-2.10 (1H, m), 2.82 (1H, d, J = 12.4Hz), 2.97-3.11 (2H, m), 3.36-3.51 (1H, m), 7.40 (1H, d, J = 7.3 Hz),7.50-7.59 (3H, m), 7.79 (1H, d, J = 8.2 Hz), 7.69-7.96 (1H, m),6.42-6.48 (1H, m), 8.97-9.24 (1H, br), 9.50-9.80 (1H, br). Hydro-chloride 253 —H

1H-NMR (CDCl3) δ ppm: 1.23-2.17 (8H, m), 1.78 (3H, s), 2.09 (3H, s),2.46-2.53 (1H, m), 3.27 (1H, d, J = 1.23 Hz), 3.66-4.18 (3H, m), 3.94(3H, s), 7.15 (1H, d, J = 2.4 Hz), 7.23 (1H, dd, J = 9.0, 2.4 Hz), 7.74(1H, brs), 7.79-7.85 (2H, m), 8.24 (1H, brs), 9.87-10.19 (2H, br)Dihydro- chloride 254 —H

1H-NMR (CDCl3) δ ppm: 1.20-2.05 (6H, m), 1.73 (3H, s), 2.00 (3H, s),2.44-2.48 (1H, m), 3.15 (1H, d, J = 10.7 Hz), 3.55-3.68 (3H, br), 7.38(1H, d, J = 6.5 Hz), 7.49-7.69 (1H, m), 7.55 (1H, d, J = 5.5 Hz), 7.92(1H, d, J = 6.6 Hz), 8.14 (1H, brs), 9.94 (2H, brs) Dihydro- chloride

TABLE 35 Absolute configuration

Ex- am- ple R¹ R⁴ NMR Salt 255 —H

1H-NMR (DMSO-d6) δ ppm: 0.95-1.82 (13H, m), 1.97-2.12 (1H, m), 2.80-3.35(4H, m), 6.07-6.72 (1H, br), 6.72-7.20 (2H, m), 7.23-7.35 (1H, m),7.35-7.53 (1H, m), 7.99 (1H, brs), 9.00-9.50 (1H, br), 9.55-10.10 (1H,br). Dihydro- chloride 256 —H

1H-NMR (DMSO-d6) δ ppm at 80° C.: 0.96-1.26 (2H, m), 1.26-1.51 (6H, m),1.61-1.61 (1H, m), 1.61-1.78 (8H, m), 1.99-2.08 (1H, m), 2.80 (1H, d, J= 12.3 Hz), 3.05-3.32 (3H, m), 3.58-4.12 (1H, br), 7.01 (1H, dd, J =3.8, 8.5 Hz), 7.08-7.18 (2H, m), 8.01 (1H, d, J = 2.1 Hz), 9.10-9.35(1H, br), 9.38-9.75 (1H, br). Dihydro- chloride 257 —H

1H-NMR (DMSO-d6) δ ppm at 80° C.: 0.98-1.27 (2H, m), 1.27-1.46 (4H, m),1.46-1.60 (2H, m), 1.60-1.80 (5H, m), 1.98-2.10 (1H, m), 2.84 (1H, d, J= 12.4 Hz), 3.05-3.35 (3H, m), 3.45-3.90 (1H, br), 7.05 (1H, d, J = 8.2Hz), 7.08-7.13 (1H, br), 7.36 (1H, d, J = 8.2 Hz), 8.03 (1H, d, J = 2.2Hz), 8.98-9.35 (1H, br), 9.35-9.72 (1H, br). Dihydro- chloride 258 —H

1H-NMR (CDCl3) δ ppm: 0.82-1.05 (2H, m), 1.07 (3H, s), 1.19-1.43 (3H,m), 1.49 (3H, s), 1.56-1.65 (1H, m), 1.88-1.90 (3H, m), 2.35-2.51 (4H,m), 2.61-2.70 (1H, m), 2.78-2.92 (2H, m), 6.83-6.89 (2H, m), 7.01 (1H,d, J = 7.8 Hz), 7.56 (1H, d, J = 2.1 Hz). — 259 —H

1H-NMR (DMSO-d6) δ ppm at 80° C.: 0.96-1.25 (2H, m), 1.25-1.60 (6H, m),1.60-1.79 (5H, m), 1.95-2.10 (1H, m), 2.78 (1H, d, J = 12.3 Hz),2.99-3.37 (3H, m), 3.93 (3H, s), 4.52-4.66 (1H, br), 8.88 (1H, d, J =8.4 Hz), 6.95 (1H, d, = 8.4 Hz), 6.98-7.09 (1H, br), 7.57 (1H, d, J =2.1 Hz), 9.02-9.40 (1H, br), 9.40-9.75 (1H, br). Dihydro- chloride 260—H

1H-NMR (DMSO-d6) δ ppm at 80° C.: 1.03-1.44 (8H, m), 1.51-1.79 (7H, m),2.00-2.10 (1H, m), 2.87 (1H, d, J = 12.4 Hz), 2.94-3.05 (1H, m),3.10-3.23 (2H, m), 4.64-5.12 (1H, br), 6.88 (1H, d, J = 1.4 Hz),7.05-7.09 (1H, m), 7.33-7.38 (1H, br), 7.59 (1H, d, J = 8.2 Hz), 7.69(1H, J = 2.2 Hz), 6.97-8.26 (1H, br), 9.45-9.52 (1H, br). Dihydro-chloride

TABLE 36 Absolute configuration

Ex- Melting am- point ple R¹ R⁴ NMR (° C.) Salt 261 —H

209.8- 214.2 Fumarate 262 —H

1H-NMR (DMSO-d6) δ ppm: 1.00-1.44 (8H, m), 1.50-1.79 (7H, m), 1.98-2.08(1H, m), 2.62-3.00 (2H, m), 3.00-3.25 (2H, m), 3.61 (3H, s), 6.62 (1H,d, J = 9.5 Hz), 7.38-7.48 (1H, m), 7.48-7.58 (2H, m), 7.91 (1H, d, J =9.5 Hz), 7.98-8.62 (1H, br), 9.14-9.37 (1H, br), 9.65-9.68 (1H, br).Dihydro- chloride 263 —H

1H-NMR (CDCl3) δ ppm: 0.87-1.03 (1H, m), 1.09 (3H, m), 1.15-1.46 (4H,m), 1.46-1.65 (8H, m), 1.65-1.68 (2H, m), 2.47-2.50 (1H, m), 2.65 (1H,d, J = 11.3 Hz), 2.76 (1H, d, J = 11.3 Hz), 2.90-3.04 (1H, m), 7.25 (1H,d, J = 7.3 Hz), 7.40 (1H, dd, J = 4.2, 8.6 Hz), 7.65-7.72 (1H, m), 7.91(1H, d, J = 6.5 Hz), 8.85 (1H, d, J = 8.5 Hz), 8.90 (1H, dd, J = 1.7,4.2 Hz). — 264 —H

1H-NMR (CDCl3) δ ppm: 0.93-1.12 (5H, m), 1.22-1.48 (3H, m), 1.55-1.70(4H, m), 1.73-1.90 (3H, m), 2.50 (1H, d, J = 11.5 Hz), 2.55-2.65 (1H,m), 2.92-3.05 (2H, m), 7.09 (1H, d, J = 4.8 Hz), 7.49-7.56 (1H, m),7.66-7.72 (1H, m), 8.05-8.10 (1H, m), 6.36 (1H, dd, J = 1.0, 8.4 Hz),8.84 (1H, d, J = 4.8 Hz). — 265 —H

1H-NMR (CDCl3) δ ppm: 0.80-1.17 (5H, m), 1.21-1.50 (6H, m), 1.61-1.86(4H, m), 2.42-2.60 (1H, m), 2.74 (1H, d, J = 11.4 Hz), 2.80-2.90 (1H,m), 2.96 (1H, d, J = 11.4 Hz), 7.31-7.39 (2H, m), 7.50 (1H, dd, J = 2.4,9.0 Hz), 8.01 (1H, d, J = 9.0 Hz), 8.06 (1H, dd, J = 1.1, 8.3 Hz), 8.51(1H, dd, J = 1.7, 4.2 Hz). — 266 —H

1H-NMR (CDCl3) δ ppm: 1.04-1.20 (4H, m), 1.20-1.48 (7H, m), 1.67-1.86(3H, m), 1.96 (1H, dd, J = 3.0, 13.0), 2.61-2.70 (1H, m), 2.82-2.95 (2H,m), 3.07 (1H, d, J = 12.0 Hz), 7.20 (1H, d, J = 1.8 Hz), 7.32 (1H, dd, J= 2.1, 8.8 Hz), 7.50 (1H, d, J = 8.8 Hz), 7.84 (1H, d, J = 8.8 Hz), 8.41(1H, d, J = 5.8 Hz), 9.09 (1H, s). —

TABLE 37 Absolute configuration

Ex- am- ple R1 R5 R6 R7 R8 R9 NMR Salt 267 —H —H —H —F —H —H 1H-NMR(DMSO-d6) δ ppm: 0.99-1.44 (8H, m), 1.44-1.80 (7H, m), 1.93-2.10Dihydro- (1H, m), 2.75-2.99 (2H, m), 2.99-3.28 (2H, m), 5.06-6.80 (1H,br), 7.10-7.33 chloride (4H, m), 8.98-9.42 (1H, br), 9.58-9.94 (1H, br).268 —H —H —OCH₃ —F —H —H 1H-NMR (DMSO-d6) δ ppm at 80° C.: 1.00-1.43(6H, m), 1.49-1.77 (7H, m), Dihydro- 1.97-2.08 (1H, m), 2.61 (1H, d, J =12.8 Hz), 2.84-2.93 (1H, m), 3.04-3.18 chloride (2H, m), 3.83 (3H, s),4.30-4.57 (1H, br), 6.68-6.74 (1H, m), 6.88 (1H, dd, J = 2.5, 7.3 Hz),7.11 (1H, dd, J = 8.6, 11.4 Hz), 8.94-9.25 (1H, br), 9.49-9.80 (1H, br).269 —H —H —Cl —CN —H —H 1H-NMR (CDCl3) δ ppm: 1.02-1.17 (1H, m),1.25-1.44 (2H, m), 1.62-2.05 Hydro- (4H, m), 1.83 (3H, s), 1.68 (3H, s),2.35-2.41 (1H, m), 2.89 (1H, d, J = 12.8 chloride Hz), 3.20 (2H, br),3.35 (1H, d, J = 12.5 Hz), 7.07 (1H, dd, J = 5.4, 2.0 Hz), 7.20 (1H, d,J = 2.0 Hz), 7.61 (1H, d, J = 8.4 Hz), 9.61 (1H, brs), 9.89 (1H, br) 270—H —H —H —Cl —H —H 1H-NMR (DMSO-d6) δ ppm: 0.96-1.45 (6H, m), 1.45-1.80(7H, m), 1.88-2.08 Dihydro- (1H, m), 2.70-3.05 (3H, m), 3.05-3.28 (1H,m), 3.50-3.94 (1H, br), 7.13 (2H, d, chloride J = 6.7 Hz), 7.39 (2H, d,J = 8.7 Hz), 8.86-9.20 (1H, br), 9.20-9.80 (1H, br). 271 —H —H —OCH₃ —Cl—H —H 1H-NMR (DMSO-d6) δ ppm: 1.00-1.45 (8H, m), 1.45-1.83 (7H, m),1.90-2.08 Hydro- (1H, m), 2.70-2.87 (1H, m), 2.87-3.08 (2H, m),3.08-3.28 (1H, m), 3.88 (3H, chloride s), 8.72 (1H, dd, J = 2.2, 8.4Hz), 6.79 (1H, d, J = 2.2 Hz), 7.38 (1H, d, J = 8.4 Hz), 8.72-9.19 (1H,br), 9.34-9.70 (1H, br). 272 —H —H —Cl —Cl —H —H 1H-NMR (CDCl3) δ ppm:0.96-1.14 (1H, m), 1.26-1.39 (2H, m), 1.55-1.78 Hydro- (3H, m), 1.62(3H, s), 1.88 (3H, s), 1.92-2.05 (1H, m), 2.30-2.35 (1H, m), 2.73chloride (1H, d, J = 12.5 Hz), 2.95-3.03 (1H, m), 3.11-3.23 (1H, m),8.28 (1H, d, J = 12.5 Hz), 7.20 (1H, dd, J = 5.5, 2.4 Hz), 7.25 (1H, d,J = 2.4 Hz), 7.39 (1H, d, J = 8.5 Hz), 9.49 (1H, br), 9.78 (1H, br) 273—CH₃ —H —Cl —Cl —H —H 1H-NMR (CDCl3) δ ppm: 1.28-1.48 (2H, m), 1.60-1.74(2H, m), 1.89 (3H, s), Hydro- 1.87-2.15 (3H, m), 1.91 (3H, s), 2.21-2.26(1H, m), 2.78 (3H, d, J = 4.9 Hz), chloride 3.22 (1H, d, J = 13.2 Hz),3.63-3.75 (1H, m), 4.32 (1H, d, J = 13.2 Hz), 4.42-4.51 (1H, m), 7.56(1H, d, J = 8.7 Hz), 7.81 (1H, dd, J = 8.7, 2.0 Hz), 8.14 (1H, d, J =2.0 Hz), 12.71 (1H, brs)

TABLE 38 Absolute configuration

Ex- am- ple R¹ R², R³ R⁴ NMR Salt 274

—H, —H

1H-NMR (CDCl3) δ ppm: 1.25-1.7 (5H, m), 1.75-1.9 (1H, m), 2.05-2.2 (2H,m), 2.3-2.4 (1H, m), 2.6-2.7 (1H, m), 2.8-2.9 (1H, m), 2.92 (1H, d, J =13.1 Hz), 3.0-3.15 (2H, m), 3.65-3.76 (1H, m), 4.20 (1H, d, J = 13.1Hz), 6.7-6.8 (2H, m), 7.1-7.2 (2H, m), 7.2-7.3 (1H, m), 7.3-7.4 (4H, m).— 275 —H —H, —H

1H-NMR (DMSO-d6) δ ppm: 1.2-1.4 (2H, m), 1.4-1.5 (1H, m), 1.5-1.95 (4H,m), 1.95-2.05 (1H, m), 2.95-3.2 (2H, m), 3.28-3.4 (1H, m), 3.4-3.6 (2H,m), 3.95-4.1 (1H, m), 6.48 (1H, br), 6.80 (1H, dd, J = 7.2, 7.2 Hz),6.9-7.0 (2H, m), 7.2-7.3 (2H, m), 9.22 (1H, br), 9.57 (1H, bs). Dihydro-chloride 276 —H —(CH₃)₃—

1H-NMR (DMSO-d6) δ ppm: 1.25-1.4 (2H, m), 1.4-2.35 (10H, m), 2.3-2.8(2H, m), 3.04 (1H, d, J = 13.3 Hz), 3.35-3.5 (1H, m), 3.67 (1H, d, J =13.4 Hz), 3.7-4.3 (2H, m), 8.95-7.05 (2H, m), 7.2-7.3 (2H, m), 8.95-9.2(1H, m), 10.1-10.3 (1H, m). Dihydro- chloride 277 —H —(CH₂)₃—

1H-NMR (CDCl3) δ ppm: 1.05-1.35 (3H, m), 1.35-1.45 (1H, m), 1.45-1.65(3H, m), 1.65-1.9 (5H, m), 1.9-2.0 (1H, m), 2.0-2.1 (1H, m), 2.2-2.3(1H, m), 2.93 (1H, d, J = 11.4 Hz), 3.25-3.35 (1H, m), 3.39 (1H, d, J =11.4 Hz), 3.7-3.8 (1H, m), 3.89 (3H, s), 7.01 (1H, d, J = 2.4 Hz), 7.04(1H, d, J = 2.5 Hz), 7.07 (1H, dd, J = 2.8, 8.8 Hz), 7.25-7.3 (1H, m),7.68 (1H, d, J = 8.9 Hz), 7.81 (1H, d, J = 9.1 Hz). — 278 —H —(CH₂)₃—

1H-NMR (DMSO-d6) δ ppm: 1.2-1.35 (2H, m), 1.4-2.15 (10H, m), 2.35-2.6(2H, m), 3.14 (1H, d, J = 12.5 Hz), 3.4-3.55 (1H, m), 3.64 (1H; d, J =13.1 Hz), 3.95-4.05 (1H, m), 4.05-4.4 (1H, m), 7.19 (1H, dd, J = 2.4,8.9 Hz), 7.31 (1H, d, J = 5.3 Hz), 7.41 (1H, d, J = 2.0 Hz), 7.69 (1H,d, J = 6.4 Hz), 7.83 (1H, d, J = 8.9 Hz), 8.9-9.1 (1H, m), 11-12.5 (1H,m). Dihydro- chloride

TABLE 39 Absolute configuration

Ex- Melting am- point ple R¹ R², R³ R⁴ NMR (° C.) Salt 279

—H, —H

1H-NMR (CDCl3) δ ppm: 1.25-1.5 (4H, m), 1.55-1.7 (1H, m), 1.75-1.85 (1H,m), 2.05-2.2 (2H, m), 2.3-2.4 (1H, m), 2.6-2.7 (1H, m), 2.8-2.9 (1H, m),2.92 (1H, d, J = 13.2 Hz), 3.0-3.15 (2H, m), 3.65-3.8 (1H, m), 4.20 (1H,d, J = 13.1 Hz), 6.7-6.8 (2H, m), 7.1-7.2 (2H, m), 7.2-7.3 (1H, m),7.3-7.4 (4H, m). — 280 —H —H, —H

1H-NMR (DMSO-d6) δ ppm: 1.2-1.4 (2H, m), 1.4-1.5 (1H, m), 1.5-1.95 (4H,m), 1.95-2.05 (1H, m), 3.0-3.2 (2H, m), 3.25-3.4 (1H, m), 3.4-3.6 (2H,m), 3.95-4.1 (1H, m), 5.65 (1H, br), 6.79 (1H, dd, J = 7.2, 7.2 Hz),6.9-7.0 (2H, m), 7.2-7.3 (2H, m), 9.16 (1H, br), 9.81 (1H, br).Dihydrochloride 281 —H —(CH₂)₃—

1H-NMR (DMSO-d6) δ ppm: 1.25-1.4 (2H, m), 1.4-2.15 (10H, m), 2.3-2.6(2H, m), 3.03 (1H, d, J = 12.5 Hz), 3.35-3.5 (1H, m), 3.65-3.85 (2H, m),3.9-4.0 (1H, m), 6.95-7.06 (2H, m), 7.2-7.3 (2H, m), 8.9-9.15 (1H, m),10.05-12.6 (1H, m). Dihydrochloride 282 —H —(CH₂)₃—

1H-NMR (CDCl3) δ ppm: 1.05-1.35 (3H, m), 1.35-1.45 (1H, m), 1.45-1.65(3H, m), 1.65-1.9 (5H, m), 1.9-2.0 (1H, m), 2.0-2.1 (1H, m), 2.2-2.3(1H, m), 2.93 (1H, d, J = 11.4 Hz), 3.25-3.38 (1H, m), 3.39 (1H, d, J =11.4 Hz), 3.7-3.8 (1H, m), 3.89 (3H, s), 7.01 (1H, d, J = 2.4 Hz), 7.04(1H, d, J = 2.6 Hz)., 7.07 (1H, dd, J = 2.6, 6.6 Hz), 7.25-7.3 (1H, m),7.58 (1H, d, J = 8.8 Hz), 7.61 (1H, d, J = 9.0 Hz). — 283 —H —(CH₂)₃—

1H-NMR (DMSO-d6) δ ppm: 1.2-1.35 (2H, m), 1.4-2.15 (10H, m), 2.4-2.6(2H, m), 3.15 (1H, d, J = 12.1 Hz), 3.4-3.55 (1H, m), 3.84 (1H, d, J =13.0 Hz), 3.95-4.1 (1H, m), 4.2-4.6 (1H, m), 7.19 (1H, dd, J = 2.4, 8.8Hz), 7.31 (1H, d, J = 5.2 Hz), 7.41 (1H, d, J = 2.0 Hz), 7.68 (1H, d, J= 5.4 Hz), 7.83 (1H, d, J = 8.9 Hz), 8.9-9.1 (1H, m), 10.1-10.3 (1H, m).Dihydrochloride

TABLE 40 Relative configuration

Ex- am- ple R¹ R² R³ R⁴ NMR Salt 284 —H —H —CH₂

1H-NMR (CDCl3) δ ppm: 1.18-1.48 (2H, m), 1.82-2.08 (8H, m), 2.56-2.61(1H, m), 3.83-3.88 (1H, m), 4.23 (1H, brs), 4.67 (3H, brs), 7.61-8.26(7H, m), 9.60-9.81 (1H, m), 11.36 (1H, br), 14.02 (1H, brs) Dihydro-chloride 285 —H —H —CH₂

1H-NMR (DMSO-d6) δ ppm: 1.02-1.43 (3H, m), 1.30 (3H, d, J = 6.4 Hz),1.44-1.88 (4H, m), 1.95-2.20 (1H, m), 2.97-3.63 (8H, m), 7.26-7.48 (1H,br), 7.50 (1H, d, J = 5.4 Hz), 7.89-8.00 (1H, br), 7.68 (1H, d, J = 5.4Hz), 8.09 (1H, d, J = 8.2 Hz), 9.28-10.12 (2H, br) Dihydro- chloride 286—H —H —CH₂

1H-NMR (DMSO-d6) δ ppm: 0.57-1.06 (1H, m), 1.17-1.35 (2H, m), 1.24 (3H,d, J = 8.3 Hz), 1.41-1.84 (4H, m), 1.82-2.07 (1H, m), 2.66-3.08 (3H, m),3.24 (1H, d, J = 12.4 Hz), 3.31-3.52 (1H, br), 7.18 (1H, dd, J = 8.6,2.1 Hz), 7.40 (1H, d, J = 2.1 Hz), 7.80 (1H, d, J = 8.8 Hz), 9.02-9.33(1H, br), 9.50-9.85 (1H, br) Hydro- chloride 287 —H —H —C₂H₅

1H-NMR (CDCl3) δ ppm: 1.05 (3H, t, J = 7.3 Hz), 1.24-1.48 (2H, m),1.51-2.14 (6H, br), 2.18-2.41 (1H, br), 2.43-2.78 (1H, m), 2.53-5.31(8H, br), 7.38-8.24 (6H, br), 9.15-10.28 (1.3h, br), 11.04-11.78 (0.3H,br), 13.30-13.79 (0.4H, br) Hydro- chloride 288 —CH₃ —H —C₂H₅

1H-NMR (CDCl3) δ ppm: 1.08 (3H, t, J = 7.5 Hz), 1.22-2.25 (10H, m),2.26-2.45 (2H, m), 2.94 (3H, s), 3.31-4.97 (4H, br), 7.88-8.02 (7H, m),12.47-13.27 (1H, br) Dihydro- chloride 289 —H —C₂H₅ —C₂H₅

1H-NMR (CDCl3) δ ppm: 0.80-2.47 (11H, m), 0.99 (3H, t, J = 7.4 Hz), 1.17(3H, t, J = 7.3 Hz), 2.86-2.75 (1H, m), 2.88-3.18 (1H, br), 3.38-3.43(1H, m), 3.86-4.01 (2H, m), 4.02-4.38 (1H, m), 7.54-7.61 (2H, m),7.80-7.96 (5H, m), 9.37 (1H, brs), 9.80-10.49 (1H, br) Dihydro- chloride290 —H —H —C₂H₅

1H-NMR (CDCl3) δ ppm: 1.07 (3H, t, J = 7.5 Hz), 1.25-1.42 (2H, m),1.48-1.88 (7H, m), 1.93-2.10 (2H, m), 2.18-2.40 (1H, m), 2.50-2.89 (1H,m), 2.91-5.05 (4H, br), 7.38-8.76 (4H, br & m), 9.19-9.82 (1H, br),11.09-11.87 (0.4H, br), 13.40-13.82 (0.6H, br) Dihydro- chloride 291 —H—C₂H₅ —C₂H₅

1H-NMR (CDCl3) δ ppm: 0.80-2.44 (11H, m), 0.97 (3H, t, J = 7.4 Hz), 1.15(3H, t, J = 7.4 Hz), 2.60-2.66 (1H, m), 2.78-3.09 (1H, m), 3.20-3.37(1H, m), 3.45-4.18 (8H, m), 7.37 (1H, d, J = 5.4 Hz), 7.49-7.71 (1H, m),7.55 (1H, d, J = 5.4 Hz), 7.55-7.98 (1H, m), 8.01-8.47 (1H, br),9.02-9.48 (1H, br), 9.69-10.18 (1H, br) Dihydro- chloride 292 —H —H—C₂H₅

1H-NMR (CDCl3) δ ppm: 1.07 (3H, t, J = 7.5 Hz), 1.23-1.50 (8H, m),1.51-2.13 (8H, m), 2.16-2.39 (1H, m), 2.50-2.71 (1H, m), 2.90-5.09 (4H,br), 7.30-7.46 (1H, m), 7.46-8.33 (3H, br), 9.10-9.91 (1H, br),10.95-11.65 (0.4H, br), 13.37-13.92 (0.8H, br) Dihydro- chloride 293 —H—C₂H₅ —C₂H₅

1H-NMR (CDCl3) δ ppm: 0.50-2.45 (10H, m), 0.97 (3H, t, J = 7.3 Hz), 1.45(3H, t, J = 7.3 Hz), 2.60-2.68 (1H, m), 2.74-3.05 (1H, m), 3.11-3.42(1H, m), 3.51-3.97 (3H, m), 7.37 (1H, d, J = 5.4 Hz), 7.50-7.68 (2H, m),7.53 (1H, d, J = 5.5 Hz), 7.63-7.88 (1H, m), 8.02-8.53 (1H, br),9.12-9.46 (1H, br), 9.66-10.18 (1H, br) Dihydro- chloride 294 —H —C₂H₅—C₂H₅

1H-NMR (CDCl3) δ ppm: 0.87-2.38 (11H, m), 0.98 (3H, t, J = 7.4 Hz), 1.14(3H, t, J = 7.2 Hz), 2.49-2.73 (1H, m), 2.73-3.11 (1H, m), 3.31-3.42(1H, m), 3.52-4.28 (3H, m), 6.52 (1H, d, J = 1.9 Hz), 7.54-7.68 (2H, m),7.71 (1H, d, J = 1.9 Hz), 7.79-8.80 (1H, br), 8.94-9.51 (1H, br),9.75-10.34 (1H, br) Dihydro- chloride 295 —H —H —C₂H₅

1H-NMR (CDCl3) δ ppm: 1.08 (3H, t, J = 7.5 Hz), 1.25-1.43 (2H, m),1.84-2.05 (8H, m), 2.15-2.34 (1H, m), 2.50-2.84 (1H, m), 3.58 (1H, d, J= 11.1 Hz), 3.84-4.04 (1H, m), 4.10-4.40 (3H, m), 7.62 (1H, d, J = 8.6Hz), 7.72 (1H, d, J = 8.8 Hz), 7.97 (1H, s), 9.25-9.53 (1H, br),10.75-11.18 (1H, br) Hydro- chloride 296 —H —H —C₂H₅

1H-NMR (DMSO-d6) δ ppm: 0.03 (3H, t, J = 7.3 Hz), 1.2-1.4 (2H, m),1.4-1.6 (3H, m), 1.8-1.9 (6H, m), 2.05-2.15 (1H, m), 2.8-2.9 (1H, m),3.25 (1H, br), 3.5-3.8 (2H, m), 4.0-4.1 (1H, m), 6.95-7.05 (2H, m),7.2-7.3 (2H m), 8.35-8.8 (1H, m), 9.3-9.5 (1H, m) Hydro- chloride

TABLE 41 Relative configuration

Ex- am- ple R¹⁰ R⁴ NMR Salt 297

1H-NMR (CDCl3) δ ppm: 0.08 (6H, s), 0.91 (9H, s), 1.04-1.35 (4H, m),1.53-1.80 (3H, m), 2.18-2.33 (2H, m), 2.60-2.76 (2H, m), 2.80-3.01 (3H,m), 3.09-3.13 (2H, m), 3.69-3.85 (2H, m), 7.29-7.48 (3H, m), 7.62-7.63(1H, m), 7.73-7.80 (3H, m) — 298

1H-NMR (CDCl3) δ ppm: 0.06 (6H, s), 0.90 (9H, s), 1.04-1.37 (6H, m),1.61-1.75 (2H, m), 1.79-1.84 (2H, m), 2.15-2.20 (1H, m), 2.32-2.40 (1H,m), 2.55-2.88 (1H, m), 2.71-2.90 (3H, m), 2.97-3.14 (2H, m),3.19-3.26(1H, m), 3.64-3.79 (2H, m), 8.93 (1H, dd, J = 8.5, 2.1 Hz),7.07 (1H, d, J = 2.1 Hz), 7.52 (1H, d, J = 5.5 Hz) — 299

1H-NMR (CDCl3) δ ppm: 0.07 (6H, s), 0.81-1.90 (3H, m), 0.90 (9H, s),1.66-1.78 (4H, m), 2.14-2.24 (2H, m), 2.46-2.54 (1H, m), 2.67-2.67 (1H,m), 2.72-2.82 (1H, m), 2.85-2.97 (4H, m), 3.86-3.81 (2H, m), 8.97 (1H,dd, J = 8.6, 2.4 Hz), 7.22 (1H, d, J = 2.4 Hz), 7.34 (1H, d, J = 8.6 Hz)— 300 —H

1H-NMR (CDCl3) δ ppm: 1.25-1.53 (2H, m), 1.61-1.70 (1H, m), 1.74-1.80(2H, m), 1.69-2.04 (2H, m), 2.36-2.43 (1H, m), 3.08-3.16 (1H, m),3.53-3.59 (1H, m), 3.65-3.73 (1H, m), 3.88-3.94 (1H, m), 4.08-4.14 (3H,m), 4.35-4.43 (2H, m), 4.61-4.75 (1H, m), 7.61 (1H, d, J = 6.7 Hz), 7.71(1H, d, J = 6.7 Hz), 8.00 (1H, brs), 12.52 (1H, brs) Hydro- chloride

TABLE 42 Relative configuration

Ex- am- ple R⁴ NMR Salt 301

1H-NMR (CDCl3) δ ppm: 1.25-1.50 (2H, m), 1.60-2.05 (5H, m), 2.35-2.70(1H, m), 2.81-5.38 (8H, br), 7.32-8.89 (7H, br), 9.47-10.31 (1H, br),10.55-11.77 (0.45H, br), 13.51-14.38 (0.55H, br) Hydro- chloride 302

1H-NMR (CDCl3) δ ppm: 1.25-1.51 (2H, m), 1.63-2.09 (5H, m), 2.50-2.58(1H, m), 3.56-3.91 (2H, m), 3.91-5.16 (4H, br), 7.48 (1H, d, J = 5.5Hz), 7.55-8.78 (3H, br), 7.66 (1H, d, J = 6.6 Hz), 9.46-10.11 (1H, br),10.94-11.83 (1H, br), 13.61-14.25 (1H, br) Dihydro- chloride 303

1H-NMR (CDCl3) δ ppm: 1.24-1.49 (2H, br), 1.51-2.00 (5H, m), 2.33-2.54(1H, m), 3.30-3.79 (6H, m), 3.81-4.15 (1H, br), 7.34 (1H, d, J = 8.6Hz), 7.50 (1H, d, J = 8.8 Hz), 7.59 (1H, s), 10.01 (1H, brs),10.14-10.56 (1H, br) Hydro- chloride

TABLE 43 Relative configuration

Ex- am- ple R¹ R², R³ R⁴ NMR Salt 304 —H —(CH₃)₂—

1H-NMR (DMSO-d6) δppm: 1.2-1.35 (2H, m), 1.4-2.1 (10H, m), 2.3-2.5 (2H,m), 3.03 (1H, d J = 13.2 Hz), 3.35-3.45 (1H, m), 3.66 (1H, d, J = 13.4Hz), 3.9-4.0 (1H, m), 4.35 (1H, br), 6.95-7.05 (2H, m), 7.2-7.3 (2H, m),8.9-9.1 (1H, m), 10.0-10.15 (1H, m). Dihydro- chloride 305 —H —(CH₂)₄—

1H-NMR (CDCl3) δppm: 1.20-1.66 (2H, m), 1.80-2.17 (10H, m), 2.29-2.37(1H, m), 2.46-2.67 (2H, m), 2.98-3.29 (1H, br), 3.33 (1H, d, J = 13.2Hz), 3.80-3.98 (1H, br), 3.98-4.41 (2H, br), 7.56-7.80 (2H, m),7.80-7.98 (4H, m), 8.11-8.71 (1H, br), 9.83-10.08 (1H, br), 10.13-10.87(1H, br) Hydro- chloride 306 —CH₃ —(CH₂)₄—

1H-NMR (COCl5) δppm: 1.20-1.38 (1H, m), 1.40-2.06 (12H, m), 2.24-2.44(2H, m), 2.58-2.89 (1H, m), 2.83 (3H, d, J = 4.6 Hz), 3.45 (1H, d, J =13.4 Hz), 3.58-3.83 (1H, m), 3.57-4.14 (1H, m), 4.08 (1H, d, J = 13.4Hz), 4.74-4.98 (1H, m), 7.55-7.86 (2H, m), 7.88-8.03 (4H, m), 8.42-8.20(1H, br), 13.33 (1H, brs) Dihydro- chloride 307 H —(CH₂)₄—

1H-NMR (CDCl3) δppm: 1.18-1.35 (1H, m), 1.41-2.17 (12H, m), 2.30-2.38(1H, m), 2.51-2.67 (2H, m), 3.00-3.32 (1H, br), 3.38 (1H, d, J = 12.4Hz), 3.65-4.47 (3H, br), 7.48 (1H, d J = 6.5 Hz), 7.61 (1H, d, J = 5.5Hz), 7.85-7.96 (1H, br), 7.99 (1H, d, J = 8.8 Hz), 5.12-6.18 (1H, br),9.85-10.02 (1H, br), 10.29-10.83 (1H, br) Dihydro- chloride 308 H—(CH₂)₄—

1H-NMR (CDCl3) δppm: 1.20-1.36 (1H, m), 1.41-2.21 (12H, m), 2.29-2.37(1H, m), 2.49-2.58 (1H, m), 2.61-2.67 (1H, m), 3.07-3.30 (1H, br), 3.38(1H, d, J = 13.1 Hz), 3.86-3.97 (1H, br), 3.98-4.32 (2H, br), 7.38 (1H,d, J = 5.6 Hz), 7.69 (1H, d, J = 5.5 Hz), 7.67-7.90 (1H, br), 7.93 (1H,d, J = 8.8 Hz), 8.11-8.93 (1H, br), 9.56-10.03 (1H, br), 10.20-10.81(1H, br) Dihydro- chloride 309 H —(CH₂)₄—

1H-NMR (CDCl3) δppm: 0.91-1.13 (1H, m), 1.23-1.38 (2H, m), 1.48-2.12(10H, m), 2.33-2.46 (3H, m), 2.76 (1H, d, J = 12.5 Hz), 2.94-3.12 (2H,m), 3.32 (1H, d, J = 12.5 Hz), 7.03 (1H, dd, J = 8.5. 2.4 Hz), 7.26 (1H,d, J = 2.4 Hz), 7.39 (1H, d, J = 8.5 Hz), 9.75 (2H, brs) Hydro- chloride310 H —(CH₂)₄—

1H-NMR (DMSO) δppm: 0.96-2.27 (18H, m), 2.97-3.59 (4H, m), 7.10 (1H, d,J = 8.7 Hz), 7.31 (1H, s), 7.78 (1H, d, J = 8.7 Hz), 6.93-9.28 (1H, br),9.32-9.67 (1H, br) Hydro- chloride 311 H —(CH₂)₅—

1H-NMR (CDCl3) δppm: 1.18-2.18 (16H, m), 2.30-2.35 (1H, m), 2.47-2.52(1H, m), 3.04 (1H, br), 3.44-3.87 (3H, m), 7.47-7.61 (3H, m), 7.83-7.89(4H, m), 9.64 (2H, br) Hydro- chloride 312 H —(CH₂)₅—

1H-NMR (CDCl3) δppm: 0.89-1.01 (1H, m), 1.08-1.70 (15H, m), 1.88-1.90(1H, m), 2.42-2.47 (1H, m), 2.54-2.73 (1H, m), 2.79 (1H, d, J = 12.2Hz), 3.00-3.05 (1H, m), 3.15 (1H, d, J = 12.2 Hz), 3.76 (3H, s),3.47-4.70 (3H, br), 8.38 (1H, d, J = 3.0 Hz), 8.49 (2H, s), 8.93 (1H,dd, J = 8.6, 1.4 Hz), 7.27 (1H, d, J = 1.4 Hz), 7.29 (1H, d, J = 3.0Hz), 7.36 (1H, d, J = 6.6 Hz) Fumarate 313 H —(CH₂)₅—

1H-NMR (CDCl3) δppm: 0.95-1/08 (1H, m), 1.23-1.45 (6H, m), 1.08-2.13(8H, m), 2.20-2.25 (1H, m), 2.35-2.40 (1H, m), 2.62-2.67 (1H, m),3.03-3.31 (4H, m), 7.03 (1H, dd, J = 8.5. 2.4 Hz), 7.26 (1H, d, J = 2.4Hz), 7.40 (1H, d, J = 8.5 Hz), 9.49 (2H, brs) Hydro- chloride

TABLE 44 Absolute configuration

Example R¹ NMR Salt 314

1H-NMR (CDCl3) δppm: 0.9-1.1 (1H, m), 1.15-1.4 (3H, m), 1.55-1.7 (2H,m), 1.75-1.85 (1H, m), 2.1-2.2 (1H, m), 2.25-2.45 (2H, m), 2.55-2.7 (1H,m), 2.7-2.8 (1H, m), 2.55-2.98 (2H, m), 3.21 (1H, d, J = 13.4 Hz), 4.18(1H, d, J = 13.4 Hz), 7.05-7.1 (2H, m), 7.2-7.35 (7H, m). — 315 —H1H-NMR (CDCl3) δppm: 0.9-1.4 (4H, m), 1.5-1.65 (2H, m), 1.7-1.9 (2H, m),2.05-2.2 — (1H, m), 2.32 (3H, s), 2.45-2.6 (2H, m), 2.8-2.9 (1H, m),2.9-3.1 (2H, m), 7.0-7.1 (2H, m), 7.2-7.3 (2H, m).

TABLE 45 Absolute configuration

Example R¹ NMR Salt 316

1H-NMR (CDCl3) δppm: 0.95-1.1 (1H, m), 1.15-1.45 (3H, m), 1.5-1.7 (2H,m), 1.75-1.85 (1H, m), 2.1-2.25 (1H, m), 2.25-2.45 (2H, m), 2.55-2.7(1H, m), 2.7-2.6 (1H, m), 2.85-3.0 (2H, m), 3.21 (1H, d, J = 13.3 Hz),4.18 (1H, d, J = 13.4 Hz), 7.0-7.1 (2H, m), 7.2-7.35 (7H, m). — 317 —H1H-NMR (DMSO-d6) δppm: 0.55-1.05 (1H, m), 1.1-1.4 (2H, m), 1.4-1.86 (3H,m), Hydrochloride 1.85-1.8 (1H, m), 1.9-2.05 (1H, m), 2.8-3.0 (2H, m),3.0-3.2 (3H, m), 3.2-3.5 (1H, m), 7.1-7.2 (2H, m), 7.35-7.45 (2H, m),9.2-9.7 (2H, m). 318 —CH₃ 1H-NMR (CDCl3) δppm: 0.9-1.4 (4H, m), 1.5-1.85(2H, m), 1.7-1.9 (2H, m), 2.05-2.2 — (1H, m), 2.32 (3H, s), 2.45-2.8(2H, m), 2.8-2.9 (1H, m), 2.9-3.1 (2H, m), 7.0-7.15 (2H, m), 7.2-7.3(2H, m).

TABLE 46 Relative configuration

Example R⁴ NMR Salt 319

1H-NMR (DMSO-d6) δppm: 1.35 (3H, s), 1.45-1.67 (6H, m), 1.87-2.00 (4H,m), 2.16-2.30 (2H, m), 2.30-3.43 (1H, m), 3.39-3.48 (1H, m), 3.62-3.72(1H, m), 3.88-3.96 (1H, m), 3.09-4.08 (1H, m), 6.05-6.75 (1H, br), 7.10(1H, s), 7.20-7.25 (1H, m), 7.25-7.34 (1H, m), 7.33-7.40 (1H, m),7.88-7.80 (3H, m), 8.22-8.35 (1H, br), 9.30-9.45 (1H, br). Dihydro-chloride 320

1H-NMR (DMSO-d6) δppm at 80° C. 1.37-1.55 (5H, m), 1.55-1.70 (4H, m),1.71-2.00 (4H, m), 2.19-2.40 (3H, m), 3.35-3.50 (1H, m), 3.52-3.88 (1H,m), 3.84-3.97 (2H, m), 5.53-5.56 (1H, br), 7.06 (1H, dd, J = 2.4. 8.9Hz), 7.26 (1H, d, J = 5.4 Hz), 7.36 (1H, d, J = 2.4 Hz), 7.80 (1H, d, J= 5.4 Hz), 7.76 (1H, d, J = 8.9 Hz), 8.07-8.42 (1H, br), 9.20-9.57 (1H,br). Dihydro- chloride 321

1H-NMR (DMSO-d6) δppm: 1.32 (3H, s), 1.43-1.61 (6H, m), 1.65-1.89 (4H,m), 2.07-2.17 (1H, m), 2.17-2.27 (1H, m), 2.27-2.40 (1H, m), 3.27-3.36(1H, m), 3.40-3.55 (1H, m), 3.79-3.93 (2H, m), 5.00-6.60 (1H, br), 6.84(2H, d, J = 5.9 Hz), 7.19 (2H, d, J = 5.9 Hz), 5.19-8.35 (1H, br),9.25-8.44 (1H, br). Dihydro- chloride 322

1H-NMR (DMSO-d6) δppm: 1.32 (3H, s), 1.40-1.63 (6H, m), 1.63-1.90 (4H,m), 2.07-2.25 (2H, m), 2.30-2.33 (1H, m), 3.27-3.38 (1H, m), 3.48-3.58(1H, m), 3.78-3.86 (1H, m), 3.86-3.95 (1H, m), 5.30-6.75 (1H, br), 6.53(1H, d, J = 3.0. 9.1 Hz), 7.02 (1H, d, J = 3.0 Hz), 7.35 (1H, d, J = 9.1Hz), 5.23-6.40 (1H, br), 9.22-9.45 (1H, br). Dihydro- chloride

TABLE 47 Relative configuration

Exam- ple R⁴ NMR Salt 323

1H-NMR (DMSO-d6) δppm: 1.39 (3H, s), 1.43-1.85 (7H, m), 1.71-1.90 (4H,m), 1.93-2.08 (1H, m), 2.35-2.45 (1H, m), 3.80-3.79 (4H, m), 5.40-6.15(1H, br), 6.90 (1H, s), 7.09-7.20 (2H, m), 7.30-7.40 (1H, m), 7.85-7.72(2H, m), 7.75 (1H, d, J = 9.0 Hz), 8.60-8.80 (1H, br), 8.80-9.00 (1H,br). Dihydro- chloride 324

1H-NMR (DMSO-d6) δppm at 80° C. 1.88-1.54 (10H, m), 1.69-2.02 (5H, m),2.41-2.50 (1H, m), 3.55-3.85 (4H, m), 4.97-5.80 (1H, br), 6.94-7.10 (1H,br), 7.16-7.40 (2H, m), 7.59 (1H, d, J = 5.4 Hz), 7.78 (1H, d, J = 5.9Hz), 8.75-8.92 (1H, br), 8.92-9.30 (1H, br). Dihydro- chloride 325

1H-NMR (DMSO-d6) δppm: 1.33-1.52 (10H, m), 1.84-1.82 (4H, m), 1.82-1.93(1H, m), 2.30-2.40 (1H, m), 3.40-3.54 (2H, m), 3.54-3.70 (2H, m),4.48-5.20 (1H, br), 5.66 (2H, d, J = 9.0 Hz), 7.19 (2H, d, J = 9.0 Hz),8.55-8.70 (1H, br), 8.75-8.92 (1H, br). Dihydro- chloride 326

1H-NMR (DMSO-d6) δppm: 1.33-1.59 (10H, m), 1.81-1.90 (5H, m), 2.33-2.45(1H, m), 3.45-3.56 (2H, m), 3.56-3.71 (2H, m), 5.05-6.00 (1H, br), 6.85(1H, dd, J = 2.8, 9.1 Hz), 6.76 (1H, d, J = 2.6 Hz), 7.34 (1H, d, J =8.1 Hz), 8.70-8.89 (1H, br), 8.00-8.15 (1H, br). Dihydro- chloride

TABLE 48 Absolute configuration

Example R⁴ NMR Salt 327

1H-NMR (DMSO-d6) δppm: 1.35 (3H, s), 1.46-1.67 (6H, m), 1.67-2.00 (4H,m), 2.16-2.30 (2H, m), 2.30-2.43 (1H, m), 3.39-3.48 (1H, m), 3.62-3.72(1H, m), 3.88-3.96 (1H, m), 3.09-4.08 (1H, m), 6.05-6.76 (1H, br), 7.10(1H, s), 7.20-7.26 (1H, m), 7.25-7.34 (1H, m), 7.33-7.40 (1H, m),7.86-7.80 (3H, m), 8.22-8.35 (1H, br), 9.20-9.45 (1H, br). Dihydro-chloride 328

1H-NMR (DMSO-d6) δppm at 80° C.: 1.37-1.55 (5H, m), 1.55-1.70 (4H, m),1.71-2.00 (4H, m), 2.19-2.40 (3H, m), 3.35-3.50 (1H, m), 3.52-3.86 (1H,m), 3.84-3.97 (2H, m), 5.53-5.86 (1H, br), 7.06 (1H dd, J = 2.4, 8.9Hz), 7.28 (1H, d, J = 5.4 Hz), 7.38 (1H, d, J = 2.4 Hz), 7.80 (1H, d, J= 6.4 Hz), 7.76 (1H, d, J = 8.9 Hz), 8.07-8.40 (1H, br), 9.26-9.57 (1H,br). Dihydro- chloride 329

1H-NMR (DMSO-d6) δppm: 1.33-1.52 (10H, m), 1.63-1.82 (4H, m), 1.82-1.93(1H, m), 2.30-2.40 (1H, m), 3.43-3.54 (2H, m), 3.54-3.70 (2H, m),4.45-5.20 (1H, br), 6.88 (2H, d, J = 9.0 Hz), 7.19 (2H, d, J = 9.0 Hz),8.55-8.70 (1H, br), 8.75-8.82 (1H, br). Dihydro- chloride 330

1H-NMR (DMSO-d6) δppm: 1.32 (3H, s), 1.40-1.83 (8H, m), 1.83-1.90 (4H,m), 2.07-2.25 (2H, m), 2.30-2.33 (1H, m), 3.28-3.35 (1H, m), 3.46-3.59(1H, m), 3.76-3.88 (1H, m), 3.86-3.95 (1H, m), 5.30-6.75 (1H, br), 8.83(1H, d, J = 3.0, 9.1 Hz), 7.02 (1H, d, J = 3.0 Hz), 7.35 (1H, d, J = 9.1Hz), 8.23-8.40 (1H, br), 9.22-9.45 (1H, br). Dihydro- chloride

TABLE 49 Absolute configuration

Example R⁴ NMR Salt 331

1H-NMR (DMSO-d6) δppm: 1.35 (3H, s), 1.46-1.67 (6H, m), 1.87-2.00 (4H,m), 2.16-2.30 (2H, m), 2.30-2.43 (1H, m), 2.59-2.48 (1H, m), 3.62-3.72(1H, m), 3.88-3.98 (1H, m), 3.99-4.08 (1H, m), 6.05-8.75 (1H, br), 7.10(1H, s), 7.20-7.25 (1H, m), 7.26-7.34 (1H, m), 7.33-7.40 (1H, m),7.66-7.80 (3H, m), 8.22-8.35 (1H, br), 9.30-9.45 (1H, br). Dihydro-chloride 332

1H-NMR (DMSO-d6) δppm at 80° C.: 1.37-1.55 (5H, m), 1.55-1.70 (4H, m),1.71-2.00 (4H, m), 2.19-2.40 (3H, m), 3.35-3.50 (1H, m), 3.52-3.88 (1H,m), 3.54-3.97 (2H, m), 5.53-5.86 (1H, br), 7.06 (1H, dd, J = 2.4, 8.8Hz), 7.28 (1H, d, J = 5.4 Hz), 7.36 (1H, d, J = 2.4 Hz), 7.60 (1H, d, J= 6.4 Hz), 7.78 (1H, d, J = 8.9 Hz), 8.07-8.40 (1H, br), 8.20-8.57 (1H,br). Dihydro- chloride 333

1H-NMR (DMSO-d6) δppm: 1.35-1.52 (10H, m), 1.84-1.82 (4H, m), 1.52-1.93(1H, m), 2.30-2.40 (1H, m), 3.40-3.54 (1H, m), 3.54-3.70 (2H, m),4.45-5.20 (1H, br), 6.55 (2H, d, J = 9.0 Hz), 7.19 (2H, d, J = 9.0 Hz),8.55-8.70 (1H, br), 8.75-8.92 (1H, br). Dihydro- chloride 334

1H-NMR (DMSO-d6) δppm: 1.32 (3H, s), 1.40-1.63 (6H, m), 1.63-1.90 (4H,m), 2.07-2.25 (2H, m), 2.30-2.33 (1H, m), 3.27-3.38 (1H, m), 3.48-3.59(1H, m), 3.75-3.88 (1H, m), 3.88-3.95 (1H, m), 5.30-6.75 (1H, br), 8.83(1H, d, J = 3.0, 9.1 Hz), 7.02 (1H, d, J = 3.0 Hz), 7.35 (1H, d, J = 9.1Hz), 8.23-8.40 (1H, br), 9.22-9.46 (1H, br). Dihydro- chloride

TABLE 50 Absolute configuration

Example R⁴ NMR Salt 335

1H-NMR (DMSO-d6) δppm: 1.39 (3H, s), 1.43-1.55 (7H, m), 1.71-1.90 (4H,m), 1.93-2.06 (1H, m), 2.36-2.45 (1H, m), 3.60-3.79 (4H, m), 6.40-6.16(1H, br), 8.90 (1H, s), 7.09-7.20 (2H, m), 7.30-7.40 (1H, m), 7.65-7.72(2H, m), 7.75 (1H, d, J = 9.0 Hz), 8.60-8.80 (1H, br), 8.90-9.00 (1H,br). Dihydro- chloride 336

1H-NMR (DMSO-d6) δppm at 80° C.: 1.38-1.54 (10H, m), 1.89-2.02 (5H, m),2.41-2.50 (1H, m), 3.55-3.85 (4H, m), 4.97-5.80 (1H, br), 6.94-7.10 (1H,br), 7.18-7.40 (2H, m), 7.59 (1H, d, J = 5.4 Hz), 7.78 (1H, d, J = 8.9Hz), 8.75-8.92 (1H, br), 8.92-9.30 (1H, br). Dihydro- chloride 337

1H-NMR (DMSO-d6) δppm: 1.33-1.52 (10H, m), 1.64-1.82 (4H, m), 1.82-1.93(1H, m), 2.30-2.40 (1H, m), 3.40-3.54 (2H, m), 3.54-3.70 (2H, m),4.45-5.20 (1H, br), 6.66 (2H, d, J = 9.0 Hz), 7.19 (2H, d, J = 9.0 Hz),8.55-8.70 (1H, br), 8.76-8.92 (1H, br). Dihydro- chloride 338

1H-NMR (DMSO-d6) δppm: 1.33-1.59 (10H, m), 1.81-1.90 (5H, m), 2.35-2.45(1H, m), 3.45-3.56 (2H, m), 3.55-3.71 (2H, m), 5.05-6.00 (1H, br), 5.65(1H, d, J = 2.8, 9.1 Hz), 6.78 (1H, d, J = 2.8 Hz), 7.34 (1H, d, J = 9.1Hz), 8.70-8.89 (1H, br), 9.00-9.16 (1H, br). Dihydro- chloride

TABLE 51 Absolute configuration

Example R⁴ NMR Salt 339

1H-NMR (DMSO-d6) δppm: 1.39 (3H, s), 1.43-1.65 (7H, m), 1.71-1.90 (4H,m), 1.93-2.05 (1H, m), 2.35-2.45 (1H, m), 3.60-3.79 (4H, m), 8.40-8.15(1H, br), 5.90 (1H, s), 7.09-7.20 (2H, m), 7.30-7.40 (1H, m), 7.65-7.72(2H, m), 7.75 (1H, d, J = 9.0 Hz), 8.60-8.80 (1H, br), 8.80-9.00 (1H,br). Dihydro- chloride 340

1H-NMR (DMSO-d6) δppm at 80° C. 1.38-1.54 (10H, m), 1.69-2.02 (5H, m),2.41-2.50 (1H, m), 3.55-3.85 (4H, m), 4.97-5.80 (1H, br), 6.94-7.10 (1H,br), 7.18-7.40 (2H, m), 7.59 (1H, d, J = 5.4 Hz), 7.75 (1H, d, J = 5.9Hz), 8.76-6.92 (1H, br), 8.92-9.30 (1H, br). Dihydro- chloride 341

1H-NMR (DMSO-d6) δppm: 1.33-1.52 (10H, m), 1.54-1.82 (4H, m), 1.82-1.93(1H, m), 2.30-2.40 (1H, m), 3.40-3.54 (2H, m), 3.64-3.70 (2H, m),4.45-5.20 (1H, br), 8.55 (2H, d, J = 9.0 Hz), 7.19 (2H, d, J = 9.0 Hz),8.55-8.70 (1H, br), 8.76-8.92 (1H, br). Dihydro- chloride 342

1H-NMR (DMSO-d6) δppm: 1.33-1.59 (10H, m), 1.61-1.90 (8H, m), 2.33-2.45(1H, m), 3.45-3.58 (2H, m), 3.56-3.71 (2H, m), 5.05-6.00 (1H, br), 8.85(1H, dd, J = 2.8, 9.1 Hz), 6.76 (1H, d, J = 2.8 Hz), 7.34 (1H, d, J =9.1 Hz), 8.78-8.89 (1H, br), 9.08-9.15 (1H, br). Dihydro- chloride

TABLE 52 Relative configuration

Example R⁴ NMR Salt 343

1H-NMR (DMSO-d6) δppm: 1.10-1.92 (14H, m), 2.23-2.44 (2H, m), 2.84 (1H,d, J = 13.3), 3.51 (1H, d, J = 13.3 Hz), 3.78-3.94 (1H, m), 4.10-4.22(1H, m), 5.80-6.20 (1H, br), 7.11 (1H, d, J = 1.8 Hz), 7.22-7.31 (1H,m), 7.36-7.50 (2H, m), 7.66-7.85 (3H, m), 8.65-8.92 (1H, br), 9.80-9.08(1H, br). Dihydro- chloride 344

1H-NMR (DMSO-d6) δppm: 1.10-1.38 (3H, m), 1.38-1.85 (8H, m), 1.85-1.92(3H, m), 2.15-2.40 (2H, m), 2.89 (1H, d, J = 13.3 Hz), 3.37 (1H, d, J =13.3 Hz), 3.77-3.95 (1H, m), 4.00-4.14 (1H, m), 7.17 (1H, d, J = 2.3,8.9 Hz), 7.28-7.38 (2H, m), 7.88 (1H, d, J = 5.4 Hz), 7.83 (1H, d, J =8.9 Hz), 8.44-8.74 (1H, br), 9.85-9.90 (1H, br). Hydro- chloride 345

1H-NMR (DMSO-d6) δppm: 1.10-1.95 (14H, m), 2.16-2.45 (2H, m), 2.82 (1H,d, J = 13.5), 3.40 (1H, d, J = 13.5 Hz), 3.70-3.89 (1H, m), 3.89-4.07(1H, m), 8.93 (2H, d, J = 9.0 Hz), 7.26 (2H, d, J = 9.0 Hz), 8.54-8.88(1H, br), 9.66-9.98 (1H, br). Hydro- chloride 346

1H-NMR (DMSO-d6) δppm: 1.10-1.90 (14H, m), 2.19-2.45 (2H, m), 2.83 (1H,d, J = 13.8 Hz), 3.50 (1H, d, J = 13.6 Hz), 3.58-3.88 (1H, br),3.94-4.07 (1H, br), 8.92 (1H, d, J = 2.8, 9.0 Hz), 7.14 (1H, d, J = 2.9Hz), 7.42 (1H, d, J = 9.0 Hz), 8.55-8.88 (1H, br), 9.62-9.98 (1H, br).Hydro- chloride

TABLE 53 Relative configuration

Example R⁴ NMR Salt 347

1H-NMR (DMSO-d6) δppm: 1.37 (3H, s), 1.42-1.66 (12H, m), 2.10-2.25 (1H,m), 3.13 (1H, d, J = 18.4 Hz), 3.26-3.53 (1H, m), 3.92-4.48 (1H, br),7.26-7.51 (4H, m), 7.78-7.92 (3H, m), 8.85-9.15 (1H, br), 9.50-9.70 (1H,br). Dihydro- chloride 348

1H-NMR (DMSO-d6) δppm: 1.00 (3H, s), 1.20-1.70 (13H, m), 1.70-1.85 (1H,m), 2.70-2.95 (4H, m), 7.05 (1H, dd, J = 2.1, 5.7 Hz), 7.34 (1H, d, J =5.4 Hz),, 7.33 (1H, d, J = 2.1 Hz), 7.87 (1H, d, J = 5.4 Hz), 7.82 (1H,d, J = 5.7 Hz). — 349

1H-NMR (DMSO-d6) δppm: 1.33 (3H, s), 1.37-1.81 (12H, m), 2.07-2.22 (1H,m), 3.00 (1H, d, J = 13.8 Hz), 3.21-3.50 (3H, m), 3.58-4.20 (1H, br),8.97 (2H, d, J = 8.6 Hz), 7.31 (2H, d, J = 8.5 Hz), 8.66-9.00 (1H, br),9.33-9.65 (1H, m). Dihydro- chloride 350

1H-NMR (DMSO-d6) δppm: 1.33 (3H, s), 1.36 (3H, s), 1.50-1.90 (9H, m),2.07-2.28 (1H, m), 3.07 (1H, d, J = 14.2 Hz), 3.32-3.86 (3H, m), 6.85(1H, dd, J = 2.8, 6.9 Hz), 7.09 (1H, d, J = 2.8 Hz), 7.43 (1H, d, J =8.9 Hz), 8.70-8.92 (1H, br), 9.35-9.58 (1H, br). Hydro- chloride

TABLE 54 Relative configuration

Example R⁵ R⁶ R⁷ R⁸ R⁹ MS(M + 1) 351 —H —H —H —H —H 245 352 —H —H —CH₃—H —H 259 353 —H —CH₃ —H —H —H 259 354 —H —F —H —H —H 263 355 —H —H —CN—H —H 270 356 —H —CH₃ —CH₃ —H —H 273 357 —H —C₂H₅ —H —H —H 273 358 —H—CH₃ —H —CH₃ —H 273 359 —H —H —C₂H₅ —H —H 273 360 —H —OCH₃ —H —H —H 275361 —H —F —H —F —H 281 362 —H —CH₃ —CN —H —H 284 363 —H —H —(CH₂)₂CH₃ —H—H 287 364 —H —CH(CH₃)₂ —H —H —H 287 365 —H —H —CH(CH₃)₂ —H —H 287 366—H —F —CN —H —H 288 367 —H —CN —H —F —H 288 368 —H —N(CH₃)₂ —H —H —H 288369 —H —H —N(CH₃)₂ —H —H 288 370 —H —OC₂H₅ —H —H —H 289 371 —H —CH₃—OCH₃ —H —H 289 372 —H —H —OCH₂CH₃ —H —H 289 373 —H —CH₃ —F —CH₃ —H 291374 —H —H —SCH₃ —H —H 291 375 —H —SCH₃ —H —H —H 291 376 —OCH₃ —H —H —F—H 293 377 —H —F —H —Cl —H 297 378 —H —F —F —F —H 299 379 —H —H —C(CH₃)₃—H —H 301 380 —H —CH₃ —OCH₃ —CH₃ —H 303 381 —H —OCH(CH₃)₂ —H —H —H 303382 —H —OCH₃ —OCH₃ —H —H 305 383 —H —H —SCH₂CH₃ —H —H 305 384 —OCH₃ —H—H —Cl —H 309 385 —H —OCH₃ —F —F —H 311 386 —H —H

—H —H 311 387 —H —CF₃ —H —H —H 313 388 —H —H —CF₃ —H —H 313 389 —Cl —H—Cl —H —H 313 390 —H —Cl —H —Cl —H 313 391 —H —CF₃ —CH₃ —H —H 327 392 —H—H

—H —H 328 393 —H —H —OCF₃ —H —H 329 394 —H —CF₃ —H —F —H 331 395 —F —H—CF₃ —H —H 331 396 —H —F —CF₃ —H —H 331 397 —F —CF₃ —H —H —H 331 398 —H—CF₃ —F —H —H 331 399 —H —CF₃ —OCH₃ —H —H 343 400 —H —CF₃ —Cl —H —H 347

TABLE 55 Relative configuration

Example R⁴ MS(M + 1) 401

285 402

285 403

287 404

299 405

302 406

303 407

303 408

310 409

313 410

316 411

317 412

333

TABLE 56 Relative configuration

Example R⁴ MS(M + 1) 413

251 414

260 415

260 416

276 417

296 418

296 419

296 420

297 421

302 422

302 423

310 424

310 425

326 426

326 427

326 428

330 429

332 430

364

TABLE 57 Absolute configuration

Example R⁵ R⁶ R⁷ R⁸ R⁹ MS(M + 1) 431 —H —H —H —H —H 245 432 —H —H —CH₃—H —H 259 433 —H —CH₃ —H —H —H 259 434 —CH₃ —H —H —H —H 259 435 —H —CN—H —H —H 270 436 —CN —H —H —H —H 270 437 —H —H —CN —H —H 270 438 —H —CH₃—CH₃ —H —H 273 439 —H —CH₃ —H —CH₃ —H 273 440 —CH₃ —CH₃ —H —H —H 273 441—H —H —C₂H₅ —H —H 273 442 —H —OCH₃ —H —H —H 275 443 —OCH₃ —H —H —H —H275 444 —CH₃ —F —H —H —H 277 445 —H —CH₃ —F —H —H 277 446 —F —H —H —CH₃—H 277 447 —H —F —CH₃ —H —H 277 448 —CH₃ —H —F —H —H 277 449 —F —H —H —F—H 281 450 —F —H —F —H —H 281 451 —H —CH₃ —CN —H —H 284 452 —H —C(O)CH₃—H —H —H 287 453 —H —H —C(O)CH₃ —H —H 287 454 —CH₃ —H —CH₃ —CH₃ —H 287455 —H —H —CH(CH₃)₂ —H —H 287 456 —F —H —CN —H —H 288 457 —H —F —CN —H—H 288 458 —H —CN —F —H —H 288 459 —H —N(CH₃)₂ —H —H —H 288 460 —H —H—N(CH₃)₂ —H —H 288 461 —CH₃ —H —OCH₃ —H —H 289 462 —H —CH₃ —OCH₃ —H —H289 463 —H —CH₃ —F —CH₃ —H 291 464 —CH₃ —F —CH₃ —H —H 291 465 —H —H—SCH₃ —H —H 291 466 —H —SCH₃ —H —H —H 291 467 —OCH₃ —H —H —F —H 293 468—CH₃ —Cl —H —H —H 293 469 —H —CH₃ —Cl —H —H 293 470 —H —Cl —CH₃ —H —H293 471 —CH₃ —H —Cl —H —H 293 472 —F —H —H —Cl —H 297 473 —H —F —H —Cl—H 297 474 —F —H —Cl —H —H 297 475 —F —F —H —F —H 299 476 —H —H—(CH₂)₃CH₃ —H —H 301 477 —H —H —C(CH₃)₃ —H —H 301 478 —H —H —CH₂N(CH₃)₂—H —H 302 479 —H —CH₂N(CH₃)₂ —H —H —H 302 480 —OCH(CH₃)₂ —H —H —H —H 303481 —H —CH₃ —OCH₃ —CH₃ —H 303 482 —H —Cl —CN —H —H 304 483 —H —OCH₃ —H—OCH₃ —H 305 484 —H —OCH₃ —OCH₃ —H —H 305 485 —OCH₃ —H —H —OCH₃ —H 305486 —OCH₃ —F —H —F —H 311 487 —H —OCH₃ —F —F —H 311 488 —OCH₃ —H —F —F—H 311 489 —H —H —OCHF₂ —H —H 311 490

—H —H —H —H 311 491 —H —H

—H —H 311 492 —H

—H —H —H 311 493 —H

—H —H —H 311 494 —CF₃ —H —H —H —H 313 495 —H —CF₃ —H —H —H 313 496 —H —H—CF₃ —H —H 313 497 —Cl —H —Cl —H —H 313 498 —H —Cl —H —Cl —H 313 499 —H—H

—H —H 314 500 —H —CH₃ —N(CH₃)₂ —CH₃ —H 316 501

—H —H —H —H 321 502 —H —H

—H —H 321 503 —H

—H —H —H 321 504 —H —Cl —OC₂H₅ —H —H 323 505 —H —H

—H —H 325 506 —H

—H —H —H 325 507 —H —H

—H —H 325 508 —H

—H —H —H 325 509 —H —CF₃ —CH₃ —H —H 327 510 —H —H

—H —H 327 511 —H —H

—H —H 327 512 —H —H

—H —H 327 513 —H —H

—H —H 328 514 —H —OCF₃ —H —H —H 329 515 —OCF₃ —H —H —H —H 329 516 —H —H—OCF₃ —H —H 329 517 —H —F —CF₃ —H —H 331 518 —H —CF₃ —F —H —H 331 519 —H—H —O(CH₂)₂N(CH₃)₂ —H —H 332 520 —H —OCH₃ —OCH₃ —OCH₃ —H 335 521

—H —H —H —H 335 522 —H —H

—H —H 335 523 —H —H

—H —H 337 524 —H

—H —H —H 337 525 —H —H

—H —H 342 526 —H —CF₃ —OCH₃ —H —H 343 527 —H —H —O(CH₂)₅CH₃ —H —H 345528 —H —H —O(CH₂)₃N(CH₃)₂ —H —H 346 529 —H —H

—H —H 347 530 —H —Cl —CF₃ —H —H 347 531 —H —CF₃ —Cl —H —H 347 532 —Cl—Cl —H —Cl —H 347 533 —H

—H —H —H 351 534

—H —H —H —H 351 535 —H

—H —H —H 351 536 —H —H

—H —H 351 537 —H —H —SO₂N(CH₃)₂ —H —H 352 538 —H —H

—H —H 353 539 —H

—H —H —H 355 540 —H —H

—H —H 358 541 —H —H —CH₂N(i-Pr)₂ —H —H 358 542 —H —CF₃ —H —CF₃ —H 381

TABLE 58 Absolute configuration

Example R⁴ MS(M + 1) 543

287 544

289 545

295 546

296 547

296 548

297 549

298 550

300 551

301 552

303 553

303 554

309 555

310 556

313 557

316 558

316 559

317 560

325 561

325 562

325 563

325 564

328 565

333 566

342 567

371 568

375 569

375

TABLE 59 Absolute configuration

Example R⁴ MS(M + 1) 570

246 571

251 572

260 573

260 574

265 575

276 576

296 577

301 578

314

TABLE 63 relative configuration

Example R⁴ NMR Salt 588

1H-NMR (DMSO-d6) δ ppm: 1.1-1.3 (2H, m), 1.3-1.45 (4H, m), 1.52 (3H, s),1.6-1.9 (4H, m), 1.95-2.1 (1H, m), 2.93 (1H, d, J = 13.1 Hz), 3.11 (1H,d, J = 13.3 Hz), 3.68 (3H, d, J = 0.6 Hz), 3.7-4.4 (3H, m), 6.82 (2H, d,J = 9.0 Hz), 6.89 (2H, d, J = 9.1 Hz), 8.09 (1H, br), 9.83 (1H, br) 2Hydrochloride

TABLE 64 absolute configuration

Example R⁴ NMR Salt 589

1H-NMR (CDCl3) δ ppm: 1.07-1.15 (18H, m), 1.17-1.34 (12H, m), 1.35-1.50(2H, m), 1.64-1.86 (4H, m), 2.82 (1H, d, J = 11.6 Hz), 3.04 (1H, d, J =11.7 Hz), 3.47-3.53 (1H, m), 3.69-3.78 (1H, m), 6.95 (1H, d, J = 2.3Hz), 7.03 (1H, dd, J = 2.4, 8.8 Hz), 7.10 (1H, d, J = 2.4 Hz), 7.23 (1H,d, J = 2.4, 9.1 Hz), 7.51 (1H, d, J = 8.9 H), 7.55 (1H, d, J = 9.1 Hz).— 590

1H-NMR (CDCl3) δ ppm: 1.13 (18H, d, J = 7.3 Hz), 1.20-1.36 (12H, m),1.36-1.64 (2H, m), 1.68-1.86 (4H, m), 2.83 (1H, d, J = 12.0 Hz), 3.12(1H, d, J = 11.9 Hz), 3.45-3.55 (1H, m), 3.75-3.85 (1H, m), 6.82 (1H, d,J = 2.3 Hz), 6.86 (1H, dd, J = 2.4, 8.7 Hz), 7.02 (1H, d, J = 2.3 Hz),7.10 (1H, dd, J = 2.4, 9.0 Hz), 7.53 (1H, d, J = 8.7 Hz), 7.59 (1H, d, J= 9.0 Hz). — 591

1H-NMR (CDCl3) δ ppm: 1.03-1.12 (18H, m), 1.12-1.32 (12H, m), 1.32-1.65(2H, m), 1.66-1.84 (4H, m), 2.82 (1H, d, J = 11.7 Hz), 3.08 (1H, d, J =11.8 Hz), 3.47-3.53 (1H, m), 3.73-3.81 (1H, m), 3.88 (3H, s), 5.17 (1H,d, J = 11.0 Hz), 5.24 (1H, d, J = 11.0 Hz), 6.94 (1H, d, J = 2.5 Hz),7.16 (1H, d, J = 9.0 Hz), 7.31 (1H, dd, J = 2.5, 9.4 Hz), 7.58 (1H, d, J= 9.0 Hz), 8.12 (1H, d, J = 9.4 Hz). — 592

1H-NMR (CDCl3) δ ppm: 1.14 (18H, d, J = 6.6 Hz), 1.19-1.35 (13H, m),1.35-1.65 (1H, m), 1.65-1.84 (4H, m), 2.83 (1H, d, J = 11.6 Hz), 3.04(1H, d, J = 11.6 Hz), 3.5-3.6 (1H, m), 3.7-3.8 (1H, m), 3.87 (3H, s),4.93 (2H, d, J = 1.0 Hz), 6.96 (1H, s), 6.99 (1H, d, J = 2.2 Hz), 7.21(1H, dd, J = 2.4, 9.0 Hz), 7.59 (1H, d, J = 9.0 Hz), 7.77 (1H, s). —

TABLE 65 absolute configuration

Example R⁴ NMR Salt 593

1H-NMR (CDCl3) δ ppm: 1.15-1.33 (9H, m), 1.33-1.50 (2H, m), 1.64-1.84(4H, m), 2.82 (1H, d, J = 11.8 Hz), 3.04 (1H, d, J = 11.8 Hz), 3.49-3.56(1H, m), 3.69-3.78 (1H, m), 6.96 (1H, d, J = 2.4 Hz), 6.99-7.06 (2H, m),7.22- 7.28 (1H, m), 7.52-7.58 (2H, m). — 594

1H-NMR (CDCl3) δ ppm: 1.17-1.36 (9H, m), 1.36-1.52 (2H, m), 1.65-1.86(4H, m), 2.83 (1H, d, J = 11.9 Hz), 3.13 (1H, d, J = 12.0 Hz), 3.45-3.55(1H, m), 3.75-3.85 (1H, m), 6.8- 6.85 (2H, m), 6.94 (1H, d, J = 2.4 Hz),7.10 (1H, d, J = 2.4, 9.1 Hz), 7.57 (1H, d, J = 8.7 Hz), 7.60 (1H, d, J= 9.1 Hz). — 595

1H-NMR (DMSO-d6) δ ppm: 1.1-1.2 (1H, m), 1.2-1.4 (8H, m), 1.5-1.9 (5H,m), 2.89 (1H, d, J = 12.4 Hz), 3.22 (1H, d, J = 12.5 Hz), 3.62 (1H, br),3.85 (3H, s), 3.95- 4.05 (1H, m), 4.85 (2H, s), 6.53 (2H, s), 7.07 (1H,d, J = 2.4 Hz), 7.28 (1H, d, J = 9.1 Hz), 7.39 (1H, dd, J = 2.5, 9.5Hz), 7.67 (1H, d, J = 9.0H), 7.98 (1H, d, J = 9.4 Hz). Fumarate 596

1H-NMR (CDCl3) δ ppm: 0.99 (1H, br), 1.15- 1.35 (8H, m), 1.35-1.5 (2H,m), 1.5-1.85 (4H, m), 2.44 (1H, br), 2.81 (1H, d, J = 11.7 Hz), 3.05(1H, d, J = 11.8H), 3.45-3.55 (1H, m), 3.7-3.8 (1H, m), 3.93 (3H, s),4.79 (2H, s), 6.98 (1H, d, J = 2.4 Hz), 7.02 (1H, s), 7.21-7.28 (1H, m),7.54 (1H, s), 7.60 (1H, d, J = 9.0 Hz). —

TABLE 66 absolute configuration

Example R⁴ NMR Salt 597

1H-NMR (CDCl3) δ ppm: 1.15-1.65 (11H, m), 1.65-1.9 (4H, m), 2.84 (1H, d,J = 12.0 Hz), 3.13 (1H, d, J = 11.9 Hz), 3.50 (1H, bs), 3.75- 3.85 (1H,m), 3.89 (3H, s), 6.89 (1H, dd, J = 2.5, 8.8 Hz), 6.92 (1H, d, J = 2.3Hz), 6.97 (1H, d, J = 2.4 Hz), 7.11 (1H, dd, J = 2.4, 9.0 Hz), 7.57 (1H,d, J = 8.8 Hz), 7.60 (1H, d, J = 9.0 Hz). — 598

1H-NMR (CDCl3) δ ppm: 1.08 (1H, br), 1.15- 1.35 (8H, m), 1.35-1.5 (2H,m), 1.65-1.85 (4H, m), 2.50 (3H, s), 2.82 (1H, d, J = 11.8 Hz), 3.07(1H, d, J = 11.7 Hz), 3.45-3.55 (1H, m), 3.7-3.8 (1H, m), 3.90 (3H, s),6.96 (1H, d, J = 2.6 Hz), 7.18 (1H, d, J = 9.0 Hz), 7.30 (1H, dd, J =2.6, 9.4 Hz), 7.51 (1H, d, J = 8.9 Hz), 7.81 (1H, d, J = 9.4 Hz). — 599

1H-NMR (CDCl3) δ ppm: 0.81-1.00 (1H, m), 1.03-1.13 (1H, m), 1.27 (3H,s), 1.33-1.43 (2H, m), 1.46 (3H, s), 1.54-1.72 (2H, m), 1.72-1.82 (1H,m), 1.85-2.0 (1H, m), 2.69 (1H, d, J = 11.1 Hz), 3.3-3.4 (2H, m), 3.75-3.85 (1H, m), 7.15 (1H, s), 7.5-7.55 (2H, m), 7.6-7.7 (2H, m), 7.7-7.8(1H, m), 8.3-8.4 (1H, m), 8.55-8.65 (1H, m), 8.65-8.75 (1H, m). — 600

1H-NMR (CDCl3) δ ppm: 1.00 (1H, br), 1.19- 1.37 (8H, m), 1.39-1.51 (2H,m), 1.68-1.79 (3H, m), 1.79-1.93 (1H, m), 2.90 (1H, d, J = 11.8 Hz),3.18 (1H, d, J = 11.9 Hz), 3.5-3.6 (1H, m), 3.8-3.9 (1H, m), 7.05 (1H,d, J = 2.1 Hz), 7.3-7.45 (3H, m), 7.8-7.95 (3H, m), 8.15 (1H, s), 8.25(1H, s). — 601

1H-NMR (DMSO-d6) δ ppm: 0.85-1.0 (1H, m), 1.0-1.1 (1H, m), 1.3-1.4 (1H,m), 1.6- 1.65 (7H, m), 1.65-1.85 (2H, m), 1.85-2.1 (2H, m), 2.59 (3H,s), 2.76 (1H, d, J = 12.6 Hz), 3.3-3.5 (1H, m), 3.51 (1H, d, J = 13.1Hz), 4.15-4.3 (1H, m), 7.02 (1H, d, J = 7.5 Hz), 7.28 (1H, d, J = 8.0Hz), 7.5-7.65 (2H, m), 7.95-8.15 (2H, m), 8.25-8.35 (1H, m), 9.6-9.8(1H, m). Hydrochloride 602

1H-NMR (DMSO-d6) δ ppm: 1.29-1.51 (6H, m), 1.56 (3H, s), 1.65-2.1 (5H,m), 3.09 (1H, d, J = 13.6 Hz), 3.62 (1H, d, J = 13.5 Hz), 3.8- 3.9 (1H,m), 4.2-4.3 (1H, m), 7.32 (1H, d, J = 2.2 Hz), 7.50 (1H, dd, J = 1.6,8.4 Hz), 7.63 (1H, dd, J = 2.5, 9.2 Hz), 7.87-7.98 (2H, m), 8.11-8.29(2H, m), 9.74 (1H, br). Hydrochloride 603

1H-NMR (DMSO-d6) δ ppm: 1.32-1.54 (6H, m), 1.58 (3H, s), 1.67-1.90 (3H,m), 1.90- 2.14 (2H, m), 3.11 (1H, d, J = 13.8 Hz), 3.71 (1H, d, J = 13.8Hz), 3.75-3.9 (1H, m), 4.25- 4.35 (1H, m), 7.29 (1H, d, J = 2.2 Hz),7.5- 7.65 (2H, m), 7.81 (1H, d, J = 8.6 Hz), 7.91 (1H, d, J = 9.2 Hz),8.25-8.45 (2H, m), 9.9- 10.1 (1H, m). Hydrochloride 604

1H-NMR (CDCl3) δ ppm: 0.96 (1H, br), 1.15- 1.35 (8H, m), 1.35-1.5 (2H,m), 1.65-1.9 (4H, m), 2.83 (1H, d, J = 11.8 Hz), 3.09 (1H, d, J = 11.8Hz), 3.45-3.55 (1H, m), 3.75-3.85 (1H, m), 3.99 (3H, s), 6.95 (1H, d, J= 2.4 Hz), 7.20 (1H, d, J = 9.0 Hz), 7.37 (1H, dd, J = 2.5, 9.4 Hz),7.56 (1H, d, J = 9.0 Hz), 8.08 (1H, d, J = 9.3 Hz). — 605

1H-NMR (DMSO-d6) δ ppm: 0.9-1.0 (1H, m), 1.1-1.2 (1H, m), 1.3-1.4 (1H,m), 1.52 (3H, s), 1.55-1.7 (4H, m), 1.7-1.85 (2H, m), 1.85- 2.05 (2H,m), 2.73 (1H, d, J = 12.5 Hz), 3.3- 3.6 (2H, m), 3.94 (3H, s), 4.15-4.3(1H, m), 6.88 (1H, d, J = 8.2 Hz), 7.06 (1H, d, J = 8.1 Hz), 7.5-7.55(1H, m), 7.55-7.6 (1H, m), 7.95 (1H, br), 8.16 (1H, dd, J = 1.0, 8.3Hz), 8.24 (1H, d, J = 8.1 Hz), 9.45-9.6 (1H, m). Hydrochloride 606

1H-NMR (DMSO-d6) δ ppm: 1.26-1.51 (6H, m), 1.57 (3H, s), 1.66-2.12 (5H,m), 3.06 (1H, d, J = 13.6 Hz), 3.57 (1H, d, J = 13.6 Hz), 3.74-3.86 (1H,m), 4.15-4.26 (1H, m), 7.05 (1H, d, J = 1.8 Hz), 7.28-7.37 (2H, m),7.43- 7.52 (1H, m), 7.75 (1H, d, J = 8.4 Hz), 7.84 (1H, d, J = 8.2 Hz),8.23 (1H, br), 9.90 (1H, br). Hydrochloride 607

1H-NMR (DMSO-d6) δ ppm: 1.28-1.52 (6H, m), 1.57 (3H, s), 1.64-1.97 (4H,m), 2.02- 2.16 (1H, m), 3.08 (1H, d, J = 13.5 Hz), 3.56 (1H, d, J = 13.6Hz), 3.8-3.9 (1H, m), 3.95-4.1 (1H, m), 7.23 (1H, d, J = 2.0 Hz),7.36-7.45 (1H, m), 7.45-7.54 (1H, m), 7.65 (1H, d, J = 2.3 Hz), 7.78(1H, d, J = 8.1 Hz), 7.97 (1H, d, J = 8.3 Hz), 8.1-8.35 (1H, m), 9.90(1H, br). Hydrochloride 608

1H-NMR (DMSO-d6) δ ppm: 1.26-1.52 (6H, m), 1.57 (3H, s), 1.66-2.02 (4H,m), 2.02- 2.12 (1H, m), 3.07 (1H, d, J = 13.4 Hz), 3.51 (1H, d, J = 13.4Hz), 3.65-3.9 (2H, m), 4.15- 4.25 (1H, m), 7.18 (1H, d, J = 2.2 Hz),7.22- 7.3 (1H, m), 7.35-7.47 (2H, m), 7.65-7.85 (3H, m), 8.1-8.3 (1H,m), 9.8-10.0 (1H, m). 2 Hydrochloride 609

1H-NMR (DMSO-d6) δ ppm: 1.06-1.16 (1H, m), 1.16-1.39 (8H, m), 1.46-1.78(4H, m), 1.78-1.93 (1H, m), 2.81 (1H, d, J = 12.2 Hz), 2.9-4.0 (5H, m),4.30-4.42 (2H, m), 6.27-6.58 (2H, m), 7.06 (1H, d, J = 2.1 Hz), 7.10(1H, dd, J = 2.6, 8.9 Hz), 7.26 (1H, d, J = 2.5 Hz), 7.35 (1H, dd, J =2.6, 9.4 Hz), 7.61-7.68 (2H, m). ½ Fumarate 610

1H-NMR (DMSO-d6) δ ppm: 1.23-1.52 (6H, m), 1.59 (3H, s), 1.64-2.03 (4H,m), 2.03- 2.16 (1H, m), 3.07 (1H, d, J = 13.3 Hz), 3.45 (1H, d, J = 14.0Hz), 3.75-3.75 (1H, m), 3.95 (3H, s), 4.1-4.2 (1H, m), 4.77 (1H, br),7.25 (1H, d, J = 2.2 Hz), 7.46 (1H, s), 7.58 (1H, dd, J = 2.4, 9.2 Hz),7.81 (1H, d, J = 9.2 Hz), 8.23 (1H, s), 8.25-8.4 (1H, m), 10.13 (1H,br). 2 Hydrochloride 611

1H-NMR (DMSO-d6) δ ppm: 1.12-1.20 (1H, m), 1.21-1.39 (8H, m), 1.47-1.79(4H, m), 1.79-1.95 (1H, m), 2.84 (1H, d, J = 12.3 Hz), 2.65-3.75 (5H,m), 3.9-4.0 (1H, m), 6.54 (2H, s), 7.12 (1H, d, J = 2.2 Hz), 7.34 (1H,dd, J = 2.2, 8.7 Hz), 7.43 (1H, dd, J = 2.4, 9.2 Hz), 7.65-7.75 (2H, m),7.80 (1H, d, J = 2.1 Hz). Fumarate 612

1H-NMR (DMSO-d6) δ ppm: 1.05-1.19 (1H, m), 1.19-1.40 (8H, m), 1.46-1.80(4H, m), 1.80-1.96 (1H, m), 2.83 (1H, d, J = 12.3 Hz), 2.9-4.3 (5H, m),6.51 (1H, s), 7.05-7.45 (4H, m), 7.49 (1H, d, J = 2.3 Hz), 7.7-7.8 (2H,m). ½ Fumarate 613

1H-NMR (DMSO-d6) δ ppm: 1.0-1.15 (2H, m), 1.3-1.4 (1H, m), 1.48 (3H, s),1.50 (3H, s), 1.55-165 (1H, m), 1.7-1.8 (2H, m), 1.8- 2.0 (2H, m),2.25-2.35 (1H, m), 2.4-2.5 (1H, m), 2.6-2.75 (2H, m), 2.95-3.1 (2H, m),3.21 (3H, s), 3.3-3.5 (1H, m), 3.78 (3H, s), 3.85- 3.95 (1H, m), 6.78(1H, d, J = 8.9 Hz), 6.93 (1H, d, J = 8.9 Hz), 7.99 (1H, br), 9.64 (1H,br). Hydrochloride 614

1H-NMR (DMSO-d6) δ ppm: 1.08-1.37 (9H, m), 1.42 (6H, s), 1.47-1.85 (5H,m), 2.76 (1H, d, J = 12.4 Hz), 2.95 (1H, d, J = 12.3 Hz), 3.53 (1H, br),3.63-3.73 (1H, m), 4.74 (2H, s), 6.52 (2H, s), 6.58 (1H, d, J = 2.7 Hz),6.65 (1H, d, J = 8.9 Hz), 6.76 (1H, dd, J = 2.8, 9.0 Hz). Fumarate

TABLE 67 absolute configuration

Example R⁴ NMR Salt 615

1H-NMR (CDCl3) δ ppm: 0.91-1.09 (3H, m), 1.20 (3H, s), 1.31-1.43 (5H,m), 1.54-1.78 (3H, m), 1.81-1.95 (1H, m), 2.55-2.65 (4H, m), 3.15 (1H,d, J = 11.2 Hz), 3.4-3.5 (1H, m), 3.65-3.7 (1H, m), 6.72-6.77 (1H, m),7.05 (1H, s), 7.13 (1H, dd, J = 7.8, 7.8 Hz), 7.37 (1H, d, J = 8.0 Hz).— 616

1H-NMR (CDCl3) δ ppm: 0.85-1.08 (3H, m), 1.21 (3H, s), 1.29-1.42 (5H,m), 1.52-1.68 (2H, m), 1.68-1.88 (2H, m), 2.58 (1H, d, J = 11.0 Hz),2.77 (3H, d, J = 0.9 Hz), 3.02-3.12 (1H, m), 3.20 (1H, d, J = 11.0 Hz),3.66 (1H, br), 6.91 (1H, d, J = 7.5 Hz), 6.98 (1H, d, J = 0.8 Hz), 7.19(1H, dd, J = 7.8, 7.8 Hz), 7.52 (1H, dd, J = 0.7, 8.0 Hz). — 617

1H-NMR (CDCl3) δ ppm: 0.90-1.08 (3H, m), 1.20 (3H, s), 1.32-1.43 (5H,m), 1.45-1.78 (3H, m), 1.81-1.95 (1H, m), 2.57 (1H, d, J = 11.1 Hz),3.14 (1H, d, J = 11.1 Hz), 3.33-3.42 (1H, m), 3.62-3.71 (1H, m), 6.71(1H, dd, J = 4.1, 8.4 Hz), 6.92 (1H, dd, J = 8.9, 8.9 Hz), 7.41 (1H, d,J = 5.4 hz), 7.46 (1H, dd, J = 3.7, 5.4 Hz). — 618

1H-NMR (CDCl3) δ ppm: 0.9-1.1 (2H, m), 1.20 (3H, s), 1.3-1.45 (5H, m),1.45-1.8 (4H, m), 1.8-1.95 (1H, m), 2.58 (1H, d, J = 11.1 Hz), 3.14 (1H,d, J = 11.1 Hz), 3.3-3.4 (1H, m), 3.6-3.7 (1H, m), 3.96 (3H, s), 6.66(1H, d, J = 8.2 Hz), 6.74 (1H, d, J = 8.2 Hz), 7.39 (1H, d, J = 5.4 Hz),7.45 (1H, d, J = 5.4 Hz). — 619

1H-NMR (CDCl3) δ ppm: 0.92-1.08 (3H, m), 1.20 (3H, s), 1.30-1.43 (5H,m), 1.47-1.78 (3H, m), 1.82-1.96 (1H, m), 2.61 (1H, d, J = 11.2 Hz),3.13 (1H, d, J = 11.2 Hz), 3.42-3.52 (1H, m), 3.63-3.71 (1H, m), 6.74(1H, d, J = 8.2 Hz), 7.21 (1H, d, J = 8.2 Hz), 7.43 (1H, d, J = 5.5 Hz),7.47 (1H, d, J = 5.5 Hz). — 620

1H-NMR (CDCl3) δ ppm: 0.94 (1H, br), 1.14- 1.33 (8H, m), 1.33-1.49 (2H,m), 1.65-1.85 (4H, m), 2.82 (1H, d, J = 11.7 Hz), 2.97 (1H, d, J = 11.6Hz), 3.45-3.55 (1H, m), 3.6-3.7 (1H, m), 7.04 (1H, d, J = 2.1 Hz), 7.10(1H, d, J = 2.2 Hz), 7.20 (1H, d, J = 5.4 Hz), 7.41 (1H, d, J = 5.5 Hz).— 621

1H-NMR (DMSO-d6) δ ppm: 1.02-1.19 (2H, m), 1.32-1.44 (1H, m), 1.51 (3H,s), 1.52 (3H, s), 1.58-1.88 (3H, m), 1.92-2.09 (2H, m), 3.00 (1H, d, J =13.0 Hz), 3.46 (1H, d, J = 13.1 Hz), 3.9-4.0 (1H, m), 3.95-4.08 (1H, m),6.96 (1H, dd, J = 2.0, 11.0 Hz), 7.41 (1H, dd, J = 2.2, 9.1 Hz), 7.46(1H, d, J = 5.4 Hz), 7.86 (1H, d, J = 5.4 Hz), 8.14 (1H, br), 9.76 (1H,br). Hydrochloride 622

1H-NMR (CDCl3) δ ppm: 0.92-1.12 (2H, m), 1.13-2.02 (13H, m), 2.66 (1H,d, J = 11.6 Hz), 3.22 (1H, br), 3.45-3.6 (1H, m), 3.77 (1H, br), 3.96(3H, s), 6.81 (1H, d, J = 7.6 Hz), 7.33 (1H, dd, J = 7.8, 7.8 Hz), 7.46(1H, d, J = 7.8 Hz), 8.13 (1H, s). — 623

1H-NMR (DMSO-d6) δ ppm: 0.94-1.12 (2H, m), 1.28-1.43 (1H, m), 1.51 (3H,s), 1.53 (3H, s), 1.58-2.07 (5H, m), 2.84 (1H, d, J = 12.6 Hz), 3.41(1H, d, J = 13.0 Hz), 3.6-3.7 (1H, m), 4.15-4.25 (1H, m), 7.11 (1H, dd,J = 6.5, 12.6 Hz), 7.77 (1H, dd, J = 3.8, 5.4 Hz), 7.84 (1H, d, J = 5.4Hz), 8.05 (1H, br), 9.85 (1H, br). Hydrochloride 624

1H-NMR (DMSO-d6) δ ppm: 1.17-1.52 (6H, m), 1.52-1.63 (3H, m), 1.63-1.74(1H, m), 1.74-1.98 (3H, m), 1.98-2.16 (1H, m), 2.33 (3H, d, J = 1.0 Hz),3.03 (1H, d, J = 13.4 Hz), 3.33-3.5 (1H, m), 3.53-3.97 (2H, m), 4.03-4.18 (1H, m), 7.03-7.12 (1H, m), 7.15 (1H, dd, J = 2.1, 8.9 Hz), 7.4-7.5(1H, m), 7.59 (1H, d, J = 8.8 Hz), 8.1-8.35 (1H, m), 9.8-10.1 (1H, m). 2Hydrochloride 625

1H-NMR (DMSO-d6) δ ppm: 1.1-1.4 (9H, m), 1.49-1.93 (6H, m), 2.31 (3H, d,J = 1.2 Hz), 2.83 (1H, d, J = 12.4 Hz), 3.19 (1H, d, J = 12.4 Hz),3.25-3.85 (3H, m), 3.85-3.95 (1H, m), 6.52 (2H, s), 7.01 (1H, d, J = 1.2Hz), 7.10 (1H, dd, J = 2.3, 9.0 Hz), 7.34 (1H, d, J = 2.2 Hz), 7.55 (1H,d, J = 8.8 Hz). Fumarate 626

1H-NMR (DMSO-d6) δ ppm: 1.09-1.17 (1H, m), 1.17-1.41 (8H, m), 1.45-1.76(4H, m), 1.76-1.89 (1H, m), 2.47 (3H, d, J = 1.1 Hz), 2.78 (1H, d, J =12.2 Hz), 3.11 (1H, d, J = 12.2 Hz), 3.47 (3H, m), 3.75-3.85 (1H, m),6.50 (1H, s), 6.90 (1H, s), 6.99 (1H, dd, J = 2.3, 8.9 Hz), 7.25 (1H, d,J = 2.2 Hz), 7.48 (1H, d, J = 8.8 Hz). ½ Fumarate

TABLE 68 absolute configuration

Example R⁴ NMR Salt 627

1H-NMR (CDCl3) δ ppm: 0.99 (1H, br), 1.20 (3H, s), 1.22 (3H, s),1.29-1.51 (4H, m), 1.68-1.82 (3H, m), 1.82-1.95 (1H, m), 2.79 (1H, d, J= 12.8 Hz), 3.35-3.45 (1H, m), 3.91 (1H, d, J = 12.8 Hz), 4.2-4.3 (1H,m), 6.66 (1H, d, J = 9.0 Hz), 7.03 (2H, s), 7.77 (1H, d, J = 8.9 Hz). —628

1H-NMR (DMSO-d6) δ ppm: 1.35-1.63 (9H, m), 1.69-1.97 (3H, m), 1.97-2.16(2H, m), 3.05-3.35 (1H, m), 3.35-4.3 (2H, m), 4.3-4.8 (2H, m), 7.1-7.35(1H, m), 7.4-7.75 (1H, m), 8.0-8.2 (1H, m), 8.25-8.7 (2H, m), 9.85-10.35(1H, m). 2 Hydrochloride 629

1H-NMR (DMSO-d6) δ ppm: 1.43-1.54 (5H, m), 1.64 (3H, s), 1.71-1.83 (2H,m), 1.83- 2.06 (2H, m), 2.06-2.17 (1H, m), 2.4-2.6 (1H, m), 3.56 (1H, d,J = 15.1 Hz), 3.85-4.0 (1H, m), 4.25 (1H, d, J = 15.0 Hz), 4.65-4.75(1H, m), 7.28 (1H, d, J = 7.2 Hz), 7.69 (1H, d, J = 5.7 Hz), 8.5-8.6(2H, m), 8.9-9.1 (1H, m), 10.35-10.65 (1H, m), 15.15 (1H, br). 2Hydrochloride

TABLE 69 absolute configuration

Example R⁴ NMR Salt 630

1H-NMR (CDCl3) δ ppm: 0.85-1.17 (3H, m), 1.20 (3H, s), 1.31 (3H, s),1.33-1.45 (2H, m), 1.5-1.78 (3H, m), 1.81-1.95 (1H, m), 2.45 (3H, d, J =1.0 Hz), 2.80 (1H, d, J = 11.5 Hz), 3.05 (1H, d, J = 11.5 Hz), 3.55-3.64(2H, m), 6.39 (1H, s), 6.56 (1H, dd, J = 0.5, 7.7 Hz), 6.99 (1H, d, J =8.2 Hz), 7.06 (1H, dd, J = 7.9, 7.9 Hz). — 631

1H-NMR (CDCl3) δ ppm: 1.10-1.27 (5H, m), 1.29 (3H, s), 1.35-1.48 (2H,m), 1.48-1.83 (5H, m), 2.77-2.89 (2H, m), 3.49-3.55 (1H, m), 3.55-3.63(1H, m), 4.01 (3H, s), 6.50 (1H, d, J = 2.0 Hz), 6.58 (1H, d, J = 2.1Hz), 6.63 (1H, d, J = 2.1 Hz), 7.53 (1H, d, J = 2.0 Hz). — 632

1H-NMR (DMSO-d6) δ ppm: 1.05-1.22 (2H, m), 1.34-1.45 (1H, m), 1.48 (3H,s), 1.53 (3H, s), 1.60-2.07 (5H, m), 3.13 (1H, d, J = 13.2 Hz), 3.28(1H, d, J = 13.4 Hz), 3.88-3.89 (1H, m), 3.89-4.02 (1H, m), 6.62 (1H,dd, J = 2.1, 12.3 Hz), 7.09 (1H, dd, J = 1.3, 8.7 Hz), 7.22 (1H, dd, J =0.7, 2.2 Hz), 7.96 (1H, d, J = 2.3 Hz), 8.05-8.2 (1H, m), 9.7-9.95 (1H,m). Hydrochloride 633

1H-NMR (DMSO-d6) δ ppm: 1.16-1.35 (2H, m), 1.35-1.45 (1H, m), 1.47 (3H,s), 1.54 (3H, s), 1.66-1.92 (3H, m), 1.92-2.14 (2H, m), 3.25 (1H, d, J =13.5 Hz), 3.45 (1H, d, J = 13.4 Hz), 3.85-4.0 (1H, m), 4.2-4.35 (1H, m),6.68 (1H, dd, J = 2.4, 12.1 Hz), 6.89-7.04 (2H, m), 8.02 (1H, d, J = 2.2Hz), 8.26 (1H, br), 9.89 (1H, br). Hydrochloride 634

1H-NMR (DMSO-d6) δ ppm: 1.18-1.36 (2H, m), 1.36-1.49 (4H, m), 1.49-1.57(3H, m), 1.62-1.94 (4H, m), 1.94-2.12 (1H, m), 3.03 (1H, d, J = 13.3Hz), 3.25-3.4 (1H, m), 3.75- 3.9 (1H, m), 3.95-4.15 (1H, m), 7.22 (1H,s), 7.37 (1H, dd, J = 2.5, 9.3 Hz), 7.62 (1H, d, J = 9.2 Hz), 7.95 (1H,s), 8.18 (1H, br), 9.6-10.1 (1H, m). Hydrochloride 635

1H-NMR (DMSO-d6) δ ppm: 0.85-1.1 (2H, m), 1.2-1.35 (7H, m), 1.45-1.85(4H, m), 1.85-2.05 (1H, m), 2.81 (1H, d, J = 12.0 Hz), 2.9-4.4 (5.5H,m), 6.52 (1.5H, s), 6.60 (1H, d, J = 8.6 Hz), 7.0-7.4 (3H, m), 8.00 (1H,d, J = 2.2 Hz). ¾ Fumarate 636

1H-NMR (DMSO-d6) δ ppm: 1.0-1.2 (2H, m), 1.35-1.44 (1H, m), 1.50 (3H,s), 1.53 (3H, s), 1.59-2.07 (5H, m), 3.05 (1H, d, J = 12.8 Hz), 3.27(1H, d, J = 13.0 Hz), 3.84 (3H, s), 3.89-4.02 (2H, m), 6.66 (1H, d, J =8.5 Hz), 6.75 (1H, d, J = 8.4 Hz), 6.93 (1H, J = 2.2 Hz), 7.92 (1H, d, J= 2.2 Hz), 8.0-8.2 (1H, m), 9.55-9.6 (1H, m). Hydrochloride 637

1H-NMR (DMSO-d6) δ ppm: 1.21-1.37 (2H, m), 1.37-1.49 (4H, m), 1.52 (3H,s), 1.63- 1.92 (4H, m), 1.92-2.10 (1H, m), 3.02 (1H, d, J = 13.2 Hz),3.29 (1H, d, J = 13.5 Hz), 3.75- 3.9 (1H, m), 3.95-4.1 (1H, m), 6.92(1H, d, J = 2.2 Hz), 7.12 (1H, d, J = 2.1 Hz), 7.16 (1H, d, J = 2.1 Hz),8.01 (1H, d, J = 2.1 Hz), 8.06 (1H, br), 9.72 (1H, br) Hydrochloride 638

1H-NMR (DMSO-d6) δ ppm: 1.18-1.37 (2H, m), 1.37-1.48 (4H, m), 1.55 (3H,s), 1.61- 1.98 (4H, m), 1.99-2.15 (1H, m), 2.38 (3H, s), 3.00 (1H, d, J= 13.3 Hz), 3.28 (1H, d, J = 13.2 Hz), 3.7-3.85 (1H, m), 3.95-4.05 (1H,m), 4.34 (1H, br), 6.40 (1H, s), 6.89 (1H, dd, J = 2.1, 8.6 Hz), 7.05(1H, d, J = 1.4 Hz), 7.33 (1H, d, J = 8.5 Hz), 8.22 (1H, br), 10.07 (1H,br). 2 Hydrochloride 639

1H-NMR (DMSO-d6) δ ppm: 1.28-1.48 (6H, m), 1.52 (3H, s), 1.64-1.93 (4H,m), 1.95- 2.06 (1H, m), 2.99 (1H, d, J = 13.6 Hz), 3.46 (1H, d, J = 13.4Hz), 3.5-3.95 (2H, m), 4.05- 4.15 (1H, m), 6.83-6.92 (2H, m), 7.01 (1H,s), 7.83 (1H, d, J = 2.1 Hz), 8.14 (1H, br), 9.82 (1H, br). 2Hydrochloride 640

1H-NMR (DMSO-d6) δ ppm: 1.18-1.49 (6H, m), 1.53 (3H, s), 1.62-1.93 (4H,m), 1.95- 2.12 (1H, m), 3.00 (1H, d, J = 13.2 Hz), 3.30 (1H, d, J = 13.2Hz), 3.7-3.85 (1H, m), 3.95- 4.1 (1H, m), 4.95 (1H, br), 6.91 (1H, dd, J= 2.1, 3.0 Hz), 6.94 (1H, d, J 2.1 Hz), 7.01 (1H, dd, J = 2.1, 14.3 Hz),7.99 (1H, d, J = 2.1 Hz), 8.14 (1H, br), 9.89 (1H, br). 2 Hydrochloride641

1H-NMR (DMSO-d6) δ ppm: 1.12-1.29 (8H, m), 1.29-1.40 (2H, m), 1.45-1.76(4H, m), 1.82-1.96 (1H, m), 2.80 (1H, d, J = 12.6 Hz), 2.85-3.85 (4H,m), 3.85-3.95 (1H, m), 6.55 (2H, s), 7.08 (1H, s), 7.12 (1H, dd, J =2.1, 9.0 Hz), 7.56 (1H, d, J = 8.9 Hz), 7.88 (1H, d, J = 0.6 Hz).Fumarate

TABLE 70

Exam- ple. R⁴ NMR Salt 642

1H-NMR (CDCl3) δppm: 1.10-1.20 (20H, m), 1.22 (3H, s), 1.25-1.36 (4H,m), 1.37-1.50 (2H, m), 1.64-1.88 (7H, m), 2.82 (1H, d, J = 11.8 Hz),3.02 (1H, d, J = 11.8 Hz), 3.45-3.55 (1H, m), 3.6-3.7 (1H, m), 6.82 (1H,s), 6.86 (1H, dd, J = 2.0, 8.9 Hz), 7.54 (1H, d, J = 8.8 Hz), 8.04 (1H,d, J = 0.9 Hz). — 643

1H-NMR (CDCl3) δppm: 1.11-1.19 (19H, m), 1.21 (3H, s), 1.23-1.32 (2H,m), 1.35 (3H, s), 1.37-1.47 (2H, m), 1.63-1.86 (6H, m), 1.90-2.04 (1H,m), 3.04 (1H, d, J = 11.9 Hz), 3.09 (1H, d, J = 12.0 Hz), 3.55-3.65 (1H,m), 3.8-3.9 (1H, m), 6.41 (1H, d, J = 7.5 Hz), 7.05 (1H, d, J = 8.5 Hz),7.16 (1H, dd, J = 7.6, 8.3 Hz), 8.26 (1H, d, J = 0.8 Hz). — 644

1H-NMR (CDCl3) δppm: 1.14-1.23 (21H, m), 1.23-1.33 (6H, m), 1.38-1.50(2H, m), 1.63- 1.88 (4H, m), 1.93-2.06 (3H, m), 2.82 (1H, d, J = 11.8Hz), 3.00 (1H, d, J = 11.8 Hz), 3.44- 3.50 (1H, m), 3.56-3.65 (1H, m),6.88-6.94 (2H, m), 7.28 (1H, d, J = 0.4 Hz), 7.42-7.47 (1H, m). — 645

1H-NMR (CDCl3) δppm: 1.02-1.17 (21H, m), 1.19 (3H, s), 1.31-1.42 (5H,m), 1.59-1.77 (6H, m), 1.79-1.92 (1H, m), 2.67 (1H, d, J = 11.3 Hz),3.09 (1H, d, J = 11.3 Hz), 3.45-3.6 (1H, m), 3.6-3.7 (1H, m), 6.39 (1H,dd, J = 3.4, 8.3 Hz), 6.65 (1H, dd, J = 3.2, 3.2 Hz), 6.72 (1H, d, J =8.2, 12.7 Hz), 7.25 (1H, d, J = 3.2 Hz). — 646

1H-NMR (CDCl3) δppm: 0.95 (1H, br), 1.15- 1.30 (26H, m), 1.32-1.49 (2H,m), 1.63-1.82 (4H, m), 1.93-2.08 (3H, m), 2.78 (1H, d, J = 11.6 Hz),2.93 (1H, d, J = 11.6 Hz), 3.45-3.55 (1H, m), 3.6-3.7 (1H, m), 6.92 (1H,d, J = 2.4 Hz), 7.07 (1H, dd, J = 2.6, 9.4 Hz), 7.23- 7.28 (1H, m), 7.46(1H, d, J = 9.4 Hz). — 647

1H-NMR (CDCl3) δppm: 1.07-1.16 (19H, m), 1.17-1.32 (8H, m), 1.32-1.48(2H, m), 1.61- 1.89 (7H, m), 2.8-2.9 (2H, m), 3.5-3.55 (1H, m),3.55-3.65 (1H, m), 6.40 (1H, d, J = 3.4 Hz), 7.21 (1H, d, J = 3.4 Hz),7.31 (1H, d, J = 2.7 Hz), 8.06 (1H, d, J = 2.7 Hz). — 648

1H-NMR (CDCl3) δppm: 1.03-1.17 (19H, m), 1.19-1.36 (8H, m), 1.36-1.49(2H, m), 1.63- 1.90 (6H, m), 1.95-2.11 (1H, m), 3.05 (1H, d, J = 12.5Hz), 3.38 (1H, d, J = 12.5 Hz), 3.45- 3.55 (1H, m), 3.95-4.05 (1H, m),6.33 (1H, d, J = 5.6 Hz), 6.54 (1H, d, J = 3.6 Hz), 7.10 (1H, d, J = 3.6Hz), 7.98 (1H, d, J = 5.6 Hz). — 649

1H-NMR (CDCl3) δppm: 1.1-1.18 (19H, m), 1.18-1.22 (4H, m), 1.34 (3H, s),1.36-1.44 (2H, m), 1.61-1.83 (7H, m), 1.85-1.98 (1H, m), 2.81 (1H, d, J= 11.5 Hz), 3.07 (1H, d, J = 11.4 Hz), 3.6-3.65 (1H, m), 3.65-3.75 (1H,m), 6.30 (1H, dd, J = 3.0, 8.2 Hz), 6.86 (1H, dd, J = 8.2, 12.0 Hz),8.24 (1H, d, J = 3.1 Hz). —

TABLE 71

Exam- ple. R⁴ NMR Salt 650

1H-NMR (CDCl3) δppm: 1.03 (1H, br), 1.15- 1.34 (8H, m), 1.34-1.52 (2H,m), 1.62-1.90 (4H, m), 2.81 (1H, d, J = 11.8 Hz), 3.05 (1H, d, J = 11.8Hz), 3.43-3.55 (1H, m), 3.69-3.81 (1H, m), 6.71 (1H, s), 6.92 (1H, d, J= 2.0, 9.0 Hz), 7.56 (1H, d, J = 8.8 Hz), 7.89 (1H, d, J = 0.9 Hz), 9.76(1H, br). — 651

1H-NMR (CDCl3) δppm: 0.95-1.25 (6H, m), 1.33 (3H, s), 1.37-1.47 (2H, m),1.64-1.80 (3H, m), 1.88-2.00 (1H, m), 3.02 (1H, d, J = 11.8 Hz), 3.09(1H, d, J = 11.8 Hz), 3.62-3.68 (1H, m), 3.83-3.92 (1H, m), 6.4-6.45(1H, m), 6.97 (1H, d, J = 8.3 Hz), 7.23 (1H, dd, J = 7.7, 8.1 Hz), 8.11(1H, d, J = 1.0 Hz), 10.05 (1H, br). — 652

1H-NMR (CDCl3) δppm: 0.95 (1H, br), 1.15- 1.33 (8H, m), 1.33-1.50 (2H,m), 1.64-1.88 (4H, m), 2.80 (1H, d, J = 11.8 Hz), 3.03 (1H, d, J = 11.8Hz), 3.45-3.55 (1H, m), 3.65-3.75 (1H, m), 6.66 (1H, s), 6.95 (1H, dd, J= 2.1, 9.0 Hz), 7.06 (1H, dd, J = 0.8, 2.0 Hz), 7.46 (1H, d, J = 9.0Hz), 8.22 (1H, bs). — 653

1H-NMR (CDCl3) δppm: 0.93-1.13 (3H, m), 1.20 (3H, s), 1.27-1.45 (5H, m),1.58-1.79 (3H, m), 1.79-1.94 (1H, m), 2.70 (1H, d, J = 11.3 Hz), 3.08(1H, d, J = 11.3 Hz), 3.6-3.7 (2H, m), 6.35 (1H, dd, J = 3.8, 8.3 Hz),6.61 (1H, dd, J = 3.3, 5.5 Hz), 6.76 (1H, dd, J = 8.3, 10.7 Hz), 7.18(1H, dd, J = 2.8, 2.8 Hz), 8.33 (1H, br). — 654

1H-NMR (CDCl3) δppm: 0.80-1.25 (6H, m), 1.28 (3H, s), 1.31-1.48 (2H, m),1.63-1.82 (4H, m), 2.81 (1H, d, J = 11.6 Hz), 2.89 (1H, d, J = 11.6 Hz),3.5-3.6 (1H, m), 3.6-3.7 (1H, m), 6.95 (1H, d, J = 2.1 Hz), 7.03 (1H,dd, J = 0.7, 2.0 Hz), 7.17 (1H, dd, J = 2.3, 9.1 Hz), 7.28 (1H, d, J =9.0 Hz), 8.64 (1H, br). — 655

1H-NMR (DMSO-d6) δppm: 1.0-1.25 (2H, m), 1.25-1.35 (7H, m), 1.45-1.9(5H, m), 2.55-4.35 (6H, m), 6.27 (1H, dd, J = 1.9, 3.3 Hz), 6.49 (1H,s), 7.33 (1H, dd, J = 2.9, 2.9 Hz), 7.40 (1H, d, J = 2.5 Hz), 8.04 (1H,d, J = 2.6 Hz), 11.30 (1H, s). 1/2 Fumarate 656

1H-NMR (CDCl3) δppm: 1.00 (1H, br), 1.18- 1.36 (7H, m), 1.36-1.52 (3H,m), 1.64-1.83 (3H, m), 1.98-2.13 (1H, m), 3.09 (1H, d, J = 12.6 Hz),3.43 (1H, d, J = 12.5 Hz), 3.52 (1H, br), 4.0-4.1 (1H, m), 6.36 (1H, d,J = 5.7 Hz), 6.51 (1H, d, J = 3.6 Hz), 7.13 (1H, d, J = 3.6 Hz), 8.03(1H, d = 5.7 Hz), 9.99 (1H, br). — 657

1H-NMR (CDCl3) δppm: 1.03-1.17 (2H, m), 1.22 (3H, s), 1.33 (3H, s),1.36-1.45 (2H, m), 1.62-1.79 (3H, m), 1.83-1.96 (1H, m), 2.83 (1H, d, J= 11.5 Hz), 3.05 (1H, d, J = 11.5 Hz), 3.65-3.7 (1H, m), 3.7-3.8 (1H,m), 6.28 (1H, dd, J = 3.3, 8.3 Hz), 6.91 (1H, dd, J = 8.3, 10.3 Hz),8.12 (1H, d, J = 3.3 Hz), 10.26 (1H, br). —

TABLE 72

Exam- ple. R⁴ NMR Salt 658

1H-NMR (CDCl3) δppm: 0.75-1.65 (11H, m), 1.65-1.9 (4H, m), 2.82 (1H, d,J = 11.7 Hz), 3.03 (1H, d, J = 11.7 Hz), 3.46-3.54 (1H, m), 3.71-3.79(1H, m), 3.80 (3H, s), 6.51 (1H, d, J = 1.6 Hz), 6.96 (1H, dd, J = 2.1,9.0 Hz), 7.02 (1H, s), 7.46 (1H, d, J = 9.0 Hz). — 659

1H-NMR (CDCl3) δppm: 0.85-1.15 (3H, m), 1.20 (3H, s), 1.32 (3H, s),1.35-1.45 (1H, m), 1.6-1.8 (4H, m), 1.85-2.0 (1H, m), 2.80 (1H, d, J =11.5 Hz), 3.10 (1H, d, J = 11.6 Hz), 3.6-3.7 (1H, m), 3.7-3.8 (1H, m),3.85 (3H, s), 6.52 (1H, d, J = 7.6 Hz), 6.89 (1H, d, J = 8.4 Hz) 7.20(1H, s), 7.25-7.3 (1H, m). — 660

1H-NMR (DMSO-d6) δppm: 1.0-1.25 (2H, m), 1.25-1.4 (7H, m), 1.45-1.9 (5H,m), 2.93 (2H, s), 3.38 (3H, br), 3.63 (1H, br), 3.70- 3.83 (4H, m), 6.28(1H, d, J = 3.4 Hz), 6.53 (2H, s), 7.39 (1H, d, J = 3.3 Hz), 7.43 (1H,d, J = 2.6 Hz), 8.10 (1H, d, J = 2.6 Hz). Fumarate 661

1H-NMR (DMSO-d6) δppm: 1.15-1.4 (9H, m), 1.5-1.8 (4H, m), 1.95-2.15 (1H,m), 3.09 (1H, d, J = 12.9 Hz), 3.43 (1H, d, J = 12.8 Hz), 3.55-3.65 (1H,m), 3.73 (3H, s), 4.05-4.15 (1H, m), 6.41 (1H, d, J = 5.6 Hz), 6.49 (1H,d, J = 3.6 Hz), 6.55 (2H, s), 7.26 (1H, d, J = 3.6 Hz), 7.93 (1H,d, J =5.6 Hz). Fumarate 662

1H-NMR (DMSO-d6) δppm: 0.95-1.15 (2H, m), 1.30-1.42 (1H, m), 1.51 (3H,s), 1.54 (3H, s), 1.57-1.66 (1H, m), 1.69-1.98 (3H, m), 1.98-2.09 (1H,m), 2.99 (1H, d, J = 12.9 Hz), 3.26 (1H, d, J = 12.8 Hz), 3.9-4.0 (1H,m), 4.05-4.2 (4H, s), 6.39 (1H, dd, J = 3.0, 8.3 Hz), 7.05 (1H, dd, J =8.2, 11.8 Hz), 8.14 (1H, br), 8.38 (1H, d, J = 2.3 Hz), 9.95 (1H, br).Hydrochloride 663

1H-NMR (DMSO-d6) δppm: 1.00-1.16 (2H, m), 1.34-1.44 (1H, m), 1.50 (3H,s), 1.52 (3H, s), 1.58-1.95 (4H, m), 1.98-2.09 (1H, m), 2.98 (1H, d, J =13.0 Hz), 3.24 (1H, d, J = 13.0 Hz), 3.85-3.95 (1H, m), 3.95-4.1 (1H,m), 4.17 (3H, s), 6.24 (1H, dd, J = 3.2, 8.0 Hz), 6.85 (1H, dd, J = 8.0,11.5 Hz), 7.95- 8.2 (1H, m), 8.74 (1H, d, J = 2.7 Hz), 9.75- 9.95 (1H,m). Hydrochloride 664

1H-NMR (DMSO-d6) δppm: 1.05-1.3 (2H, m), 1.3-1.45 (7H, m), 1.5-1.7 (2H,m), 1.7- 1.9 (3H, m), 2.97 (1H, d, J = 12.4 Hz), 3.17 (1H, d, J = 12.7Hz), 3.72 (1H, br), 3.81 (3H, s), 3.9-4.0 (1H, m), 6.58 (6H, s), 6.98(1H, d, J = 2.0 Hz), 7.14 (1H, dd, J = 2.2, 9.1 Hz), 7.49 (1H, d, J =9.0 Hz), 8.10 (1H, s). 3 Fumarate 665

1H-NMR (DMSO-d6) δppm: 1.05-1.15 (1H, m), 1.15-1.35 (9H, m), 1.45-1.75(3H, m), 1.75-1.9 (1H, m), 2.80 (1H, d, J = 11.9 Hz), 3.0-3.6 (4H, m),3.77 (3H, s), 3.8-3.9 (1H, m), 6.51 (1H, s), 6.90 (1H, d, J = 1.8 Hz),7.03 (1H, dd, J = 2.0, 8.9 Hz), 7.43 (1H, d, J = 8.8 Hz), 7.99 (1H, s).1/2 Fumarate

TABLE 73

Exam- ple. R⁴ NMR Salt 666

1H-NMR (DMSO-d6) δppm: 1.00-1.25 (2H, m), 1.31-1.42 (1H, m), 1.46 (3H,s), 1.49 (3H, s), 1.58-1.69 (1H, m), 1.69-1.84 (2H, m), 1.84-2.05 (3H,m), 2.05-2.2 (1H, m), 2.70-2.92 (5H, m), 3.24 (1H, d, J = 13.0 Hz),3.45-3.57 (1H, m), 3.80-3.93 (1H, m), 6.53 (1H, dd, J = 2.0, 11.6 Hz),6.66-6.76 (1H, m), 7.9-8.2 (1H, m), 9.7-10.0 (1H, m). Hydrochloride 667

1H-NMR (DMSO-d6) δppm: 1.00-1.21 (2H, m), 1.29-1.41 (1H, m), 1.48 (6H,s), 1.55- 1.67 (1H, m), 1.67-2.06 (5H, m), 2.07-2.21 (1H, m), 2.70 (1H,d, J = 12.7 Hz), 2.78-3.00 (4H, m), 3.21-3.39 (2H, m), 3.78-3.89 (1H,m), 6.74 (1H, dd, J = 4.4, 8.6 Hz), 6.88 (1H, dd, J = 8.6, 8.6 Hz), 8.01(1H, br), 9.74 (1H, br). Hydrochloride 668

1H-NMR (DMSO-d6) δppm: 1.10-1.24 (1H, m), 1.34-1.42 (1H, m), 1.45 (3H,s), 1.48 (3H, s), 1.58-2.03 (6H, m), 2.03-2.19 (1H, m), 2.72-2.95 (5H,m), 3.27 (1H, d, J = 12.9 Hz), 3.38-3.55 (1H, m), 3.79-3.95 (1H, m),4.28-4.11 (1H, m), 6.72 (1H, d, J = 1.5 Hz), 6.94 (1H, s), 7.9-8.1 (1H,m), 9.6-9.8 (1H, m). Hydrochloride 669

1H-NMR (DMSO-d6) δppm: 1.20-1.48 (6H, m), 1.51 (3H, s), 1.63-1.93 (4H,m), 1.93- 2.10 (1H, m), 2.96 (1H, d, J = 13.4 Hz), 3.29 (1H, d, J = 14.0Hz), 3.7-3.85 (1H, m), 3.9- 4.05 (1H, m), 6.70 (1H, dd, J = 2.5, 8.9Hz), 7.12 (1H, d, J = 2.4 Hz), 7.23 (1H, d, J = 8.9 Hz), 8.15 (1H, br),9.86 (1H, br). Hydrochloride 670

1H-NMR (DMSO-d6) δppm: 1.1-1.25 (9H, m), 1.25-1.4 (1H, m), 1.45-1.75(4H, m), 1.9- 2.05 (1H, m), 2.92 (1H, d, J = 12.2 Hz), 3.06 (1H, d, J =12.3 Hz), 3.1-3.63 (3H, m), 3.63- 3.70 (1H, m), 6.57 (2H, s), 6.71 (1H,d, J = 8.6 Hz), 6.75-6.81 (1H, m), 7.04 (1H, dd, J = 8.3, 8.3 Hz).Fumarate 671

1H-NMR (DMSO-d6) δppm: 1.15-1.31 (2H, m), 1.35-1.46 (4H, m), 1.50 (3H,s), 1.61- 1.87 (4H, m), 1.93-2.07 (1H, m), 2.92 (1H, d, J = 13.2 Hz),3.11 (1H, d, J = 13.2 Hz), 3.7-3.8 (1H, m), 3.8-3.9 (1H, m), 5.88-5.95(2H, m), 6.32 (1H, d, J = 2.4, 8.5 Hz), 6.71 (1H, d, J = 2.4 Hz), 6.76(1H, d, J = 8.5 Hz), 7.9-8.15 (1H, m), 9.7-9.9 (1H, m). Hydrochloride

TABLE 74

Exam- ple. R⁴ NMR Salt 672

1H-NMR (CDCl3) δppm: 1.02-1.15 (19H, m), 1.15-1.28 (11H, m), 1.29-1.46(2H, m), 1.60- 1.76 (4H, m), 2.67 (1H, d, J = 11.6 Hz), 2.83 (1H, d, J =11.6 Hz), 3.4-3.55 (2H, m), 6.69- 6.74 (2H, m), 6.74-6.79 (2H, m). — 673

1H-NMR (CDCl3) δppm: 1.11 (18H, d, J = 7.0 Hz), 1.16-1.33 (11H, m),1.33-1.59 (3H, m), 1.65-1.78 (4H, m), 2.68 (1H, d, J = 11.8 Hz), 2.97(1H, d, J = 11.9 Hz), 3.4-3.45 (1H, m), 3.55-3.6 (1H, m), 6.28 (1H, dd,J = 1.9, 7.6 Hz), 6.37 (1H, dd, J = 2.3, 2.3 Hz), 6.43 (1H, dd, J = 2.4,7.8 Hz), 7.03 (1H, dd, J = 8.1, 8.1 Hz). — 674

1H-NMR (CDCl3) δppm: 1.04-1.15 (19H, m), 1.15-1.30 (11H, m), 1.32-1.47(2H, m), 1.47- 1.77 (4H, m), 2.70 (1H, d, J = 11.7 Hz), 2.92 (1H, d, J =11.7 Hz), 3.41-3.48 (1H, m), 3.54- 3.63 (1H, m), 3.75 (3H, s), 4.78-4.88(2H, m), 6.65 (1H, dd, J = 3.0, 8.7 Hz), 6.71 (1H, d, J = 8.8 Hz), 7.22(1H, d, J = 2.9 Hz). — 675

1H-NMR (CDCl3) δppm: 1.06-1.14 (18H, m), 1.15-1.29 (12H, m), 1.29-1.48(2H, m), 1.58- 1.76 (4H, m), 2.65 (1H, d, J = 11.8 Hz), 2.83 (1H, d, J =11.6 Hz), 3.35-3.45 (1H, m), 3.45- 3.55 (1H, m), 6.40-6.48 (1H, m), 6.55(1H, dd, J = 2.9, 14.1 Hz), 6.79 (1H, dd, J = 9.4, 9.4 Hz). — 676

1H-NMR (CDCl3) δppm: 1.11 (18H, d, J = 7.3 Hz), 1.16-1.21 (4H, m),1.21-1.33 (7H, m), 1.34-1.47 (2H, m), 1.47-1.78 (5H, m), 2.66 (1H, d, J= 11.6 Hz), 2.81 (1H, d, J = 11.6 Hz), 3.4-3.55 (2H, m), 6.61 (1H, d, J= 3.0, 8.9 Hz), 6.78 (1H, d, J = 8.9 Hz), 6.81 (1H, d, J = 3.0 Hz). —677

1H-NMR (CDCl3) δppm: 1.06-1.11 (18H, m), 1.11-1.22 (7H, m), 1.23 (3H,s), 1.25-1.80 (8H, m), 2.71 (1H, d, J = 11.8 Hz), 3.01 (1H, d, J = 11.9Hz), 3.4-3.5 (1H, m), 3.6-3.7 (1H, m), 4.73 (2H, s), 6.79-6.85 (2H, m),7.18- 7.23 (2H, m), — 678

1H-NMR (CDCl3) δppm: 1.05-1.12 (18H, m), 1.12-1.48 (13H, m), 1.48-1.82(5H, m), 2.70 (1H, d, J = 11.9 Hz), 2.99 (1H, d, J = 12.0 Hz), 3.35-3.45(1H, m), 3.55-3.65 (1H, m), 4.77 (2H, s), 6.47 (1H, dd, J = 2.4, 13.9Hz), 6.61 (1H, dd, J = 2.4, 8.6 Hz), 7.32 (1H, dd, J = 8.8, 8.8 Hz). —679

1H-NMR (CDCl3) δppm: 1.03 (18H, d, J = 2.4 Hz), 1.13-1.27 (9H, m),1.27-1.77 (6H, m), 2.67 (1H, d, J = 11.5 Hz), 2.80 (1H, d, J = 11.5 Hz),3.4-3.55 (2H, m), 4.96 (2H, s), 6.42 (1H, d, J = 2.8 Hz), 6.70 (1H, dd,J = 2.9, 8.8 Hz), 6.80 (1H, d, J = 8.8 Hz). —

TABLE 75

Exam- ple. R⁴ NMR Salt 680

1H-NMR (CDCl3) δppm: 1.02-1.30 (9H, m), 1.30-1.49 (2H, m), 1.50-1.83(4H, m), 2.70 (1H, d, J = 10.4 Hz), 2.81 (1H, d, J = 11.4 Hz), 3.4-3.6(2H, m), 6.75 (4H, bs). — 681

1H-NMR (CDCl3) δppm: 1.16-1.30 (8H, m), 1.30-1.49 (3H, m), 1.60-1.83(4H, m), 2.71 (1H, d, J = 12.0 Hz), 3.03 (1H, d, J = 12.0 Hz), 3.38-3.45(1H, m), 3.56-3.68 (1H, m), 6.17- 6.23 (1H, m), 6.33 (1H, dd, J = 2.3,2.3 Hz), 6.43 (1H, dd, J = 2.2, 8.3 Hz), 7.06 (1H, dd, J = 8.1, 8.1 Hz).— 682

1H-NMR (DMSO-d6) δppm: 1.1-1.25 (2H, m), 1.3-1.4 (7H, m), 1.5-1.9 (5H,m), 2.87 (1H, d, J = 12.4 Hz), 2.97 (1H, d, J = 12.6 Hz), 3.63-3.78 (5H,m), 4.44 (2H, s), 6.54 (3H, s), 6.73 (1H, dd, J = 2.9, 8.8 Hz), 6.80(1H, d, J = 8.8 Hz), 6.99 (1H, d, J = 2.8 Hz). 3/2 Fumarate 683

1H-NMR (CDCl3) δppm: 1.09-2.34 (16H, m), 2.81 (1H, d, J = 12.1 Hz),2.85-3.1 (1H, m), 3.5-3.6 (1H, m), 3.6-3.75 (1H, m), 6.73 (1H, dd, J =2.8, 8.9 Hz), 6.81 (1H, d, J = 2.8 Hz), 6.92 (1H, d, J = 8.8 Hz). — 684

1H-NMR (CDCl3) δppm: 1.15-1.60 (12H, m), 1.61-1.83 (4H, m), 2.72 (1H, d,J = 12.0 Hz), 3.03 (1H, d, J = 11.9 Hz), 3.4-3.45 (1H, m), 3.6-3.7 (1H,m), 4.56 (2H, s), 6.80-6.86 (2H, m), 7.20-7.25 (2H, m). — 685

1H-NMR (CDCl3) δppm: 0.92 (1H, br), 1.16- 1.36 (8H, m), 1.37-1.48 (2H,m), 1.57 (1H, br), 1.62-1.84 (4H, m), 2.71 (1H, d, J = 12.0 Hz), 3.02(1H, d, J = 12.0H), 3.35-3.45 (1H, m), 3.55-3.65 (1H, m), 4.62 (2H, s),6.51 (1H, dd, J = 2.5, 14.0 Hz), 6.59 (1H, dd, J = 2.5, 8.5 Hz), 7.19(1H, dd, J = 8.8, 8.8 Hz). — 686

1H-NMR (CDCl3) δppm: 0.92-1.02 (1H, m), 1.02-1.18 (7H, m), 1.19-1.32(1H, m), 1.35- 1.66 (5H, m), 1.69-1.83 (1H, m), 2.60 (1H, d, J = 11.3Hz), 2.69 (1H, d, J = 11.3 Hz), 3.32 (1H, br), 3.41-3.50 (1H, m), 4.43(2H, d, J = 4.6 Hz), 4.88 (1H, t, J = 5.4 Hz), 6.55 (1H, dd, J = 2.9,8.7 Hz), 6.60 (1H, d, J = 8.6 Hz), 6.83 (1H, d, J = 2.7 Hz), 8.55 (1H,s). —

TABLE 76

Example R⁵ R⁶ R⁷ R⁸ R⁹ NMR Salt 687 —H —H —OCH3 —H —H 1H-NMR (DMSO-d6) 2Hydrochloride δppm: 1.1-1.3 (2H, m), 1.35- 1.45 (4H, m), 1.52 (3H, s),1.6-1.9 (4H, m), 1.95-2.1 (1H, m), 2.93 (1H, d, J = 13.1 Hz), 3.10 (1H,d, J = 13.0 Hz), 3.68 (3H, s), 3.7-3.9 (2H, m), 4.35- 5.75 (1H, m),6.75-6.85 (2H, m), 6.85-6.95 (2H, m), 8.11 (1H, br), 9.92 (1H, br). 688—CH3 —Cl —H —H —H 1H-NMR (CDCl3) δppm: — 0.93-1.1 (2H, m), 1.17 (3H, s),1.31 (3H, s), 1.35-1.43 (3H, s), 1.55-1.75 (3H, m), 1.78-1.93 (1H, m),2.37 (3H, s), 2.42 (1H, d, J = 11.0 Hz), 2.83-2.91 (1H, m), 3.10 (1H, d,J = 11.0 Hz), 3.5-3.6 (1H, m), 6.79 (1H, dd, J = 2.1, 7.1 Hz), 6.99-7.09 (2H, m). 689 —CH3 —H —H —H —H 1H-NMR (DMSO-d6) Hydrochloride δppm:1.0-1.17 (2H, m), 1.3- 1.43 (1H, m), 1.49 (3H, s), 1.52 (3H, s),1.56-1.68 (1H, m), 1.68-1.87 (2H, m), 1.87-2.1 (2H, m), 2.30 (3H, s),2.62 (1H, d, J = 12.6 Hz), 3.11-3.23 (1H, m), 3.25-3.45 (1H, m),3.78-3.92 (1H, m), 6.92-7.04 (2H, m), 7.08- 7.22 (2H, m), 8.03 (1H, br),9.65-9.95 (1H, m).″ 690 —H —H —CH3 —H —H 1H-NMR (DMSO-d6) 2Hydrochloride δppm: 1.18-1.35 (2H, m), 1.35-1.48 (4H, m), 1.52 (3H, s),1.62-1.9 (4H, m), 1.98-2.04 (1H, m), 2.19 (3H, s), 2.91 (1H, d, J = 13.3Hz), 3.25 (1H, d, J = 13.3 Hz), 3.7-3.8 (1H, m), 3.9- 4.0 (1H, m),4.1-4.45 (1H, m), 6.8-6.87 (2H, m), 6.98-7.07 (2H, m), 8.05- 8.25 (1H,m), 9.8-10.05 (1H, m). 691 —CH3 —CH3 —H —H —H 1H-NMR (DMSO-d6)Hydrochloride δppm: 0.98-1.15 (2H, m), 1.3-1.42 (1H, m), 1.49 (3H, s),1.52 (3H, s), 1.55- 1.67 (1H, m), 1.67-1.83 (2H, m), 1.83-2.008 (2H, m),2.20 (3H, s), 2.22 (3H, s), 2.59 (1H, d, J = 12.6 Hz), 3.05-3.15 (1H,m), 3.25- 3.4 (1H, m), 3.82-3.96 (1H, m), 6.82 (1H, d, J = 7.8 Hz), 6.91(1H, d, J = 7.4 Hz), 7.03 (1H, dd, J = 7.7, 7.7 Hz), 7.98 (1H, br),9.65- 9.8 (1H, m). 692 —H —CH3 —Cl —H —H 1H-NMR (DMSO-d6) 2Hydrochloride δppm: 1.22-1.47 (6H, m), 1.53 (3H, s), 1.63-1.93 (4H, m),1.97-2.08 (1H, m), 2.27 (3H, s), 2.93 (1H, d, J = 13.6 Hz), 3.36 (1H, d,J = 13.5 Hz), 3.7-3.8 (1H, m), 3.8-4.1 (2H, m), 6.79 (1H, dd, J = 3.0,8.9 Hz), 6.93 (1H, d, J = 2.9 Hz), 7.20 (1H, d, J = 8.8 Hz), 8.1-8.3(1H, m), 9.85-10.05 (1H, m). 693 —H —CH3 —F —H —H 1H-NMR (DMSO-d6) 2Hydrochloride δppm: 1.16-1.33 (2H, m), 1.36-1.45 (4H, m), 1.52 (3H, s),1.62-1.9 (4H, m), 2.0-2.08 (1H, m), 2.18 (3H, d, J = 1.7 Hz), 2.93 (1H,d, J = 13.3 Hz), 3.21 (1H, d, J = 13.2 Hz), 3.7-3.8 (1H, m), 3.9-4.0(1H, m), 4.15- 4.55 (1H, m), 6.72-6.8 (1H, m), 6.81-6.89 (1H, m), 6.97(1H, dd, J = 9.1, 9.1 Hz), 8.05-8.25 (1H, m), 9.85-10.1 (1H, m). 694—CH3 —F —H —H —H 1H-NMR (DMSO-d6) Hydrochloride δppm: 1.0-1.2 (2H, m),1.3-1.45 (1H, m), 1.49 (3H, s), 1.51 (3H, s), 1.56- 1.84 (3H, m),1.84-2.06 (2H, m), 2.20 (3H, d, J = 2.2 Hz), 2.67 (1H, d, J = 12.7 Hz),3.15-3.25 (1H, m), 3.29-3.42 (1H, m), 3.85- 4.0 (1H, m), 6.83 (1H, d, J= 8.0 Hz), 6.89 (1H, dd, J = 8.8, 8.8 Hz), 7.16 (1H, dd, J = 7.9, 15.3Hz), 8.02 (1H, br), 9.72 (1H, br). 695 —H —Cl —H —H —H 1H-NMR (DMSO-d6)Hydrochloride δppm: 1.25-1.46 (6H, m), 1.52 (3H, s), 1.63-1.95 (4H, m),1.95-2.1 (1H, m), 2.95 (1H, d, J = 13.7 Hz), 3.47 (1H, d, J = 13.6 Hz),3.7-3.8 (1H, m), 4.0-4.1 (1H, m), 6.77 (1H, dd, J = 1.4, 7.8 Hz), 6.90(1H, d, J = 2.2, 8.4 Hz), 6.96-7.01 (1H, m), 7.21 (1H, dd, J = 8.1, 8.1Hz), 8.17 (1H, br), 9.85 (1H, br). 696 —CH3 —OCH3 —H —H —H 1H-NMR(DMSO-d6) Hydrochloride δppm: 1.0-1.2 (2H, m), 1.3-1.4 (1H, m), 1.48(3H, s), 1.51 (3H, s), 1.55-1.65 (1H, m), 1.65-1.85 (2H, m), 1.85-2.05(2H, m), 2.13 (3H, s), 2.62 (1H, d, J = 12.6 Hz), 3.1-3.2 (1H, m),3.3-3.4 (1H, m), 3.76 (3H, s), 3.8-3.9 (1H, m), 6.61 (1H, d, J = 7.9Hz), 6.72 (1H, d, J = 8.1 Hz), 7.10 (1H, dd, J = 8.1, 8.1 Hz), 8.01 (1H,br), 9.71 (1H, br). 697 —H —Cl —CH3 —H —H 1H-NMR (DMSO-d6) Hydrochlorideδppm: 1.24-1.47 (6H, m), 1.51 (3H, s), 1.63-1.91 (4H, m), 1.91-2.08 (1H,m), 2.20 (3H, s), 2.91 (1H, d, J = 13.5 Hz), 3.23-3.42 (1H, m),3.66-3.80 (1H, m), 3.94-4.08 (1H, m), 6.84 (1H, dd, J = 2.6, 8.5 Hz),6.97 (1H, d, J = 2.6 Hz), 7.16 (1H, d, J = 8.6 Hz), 8.12 (1H, br), 9.82(1H, br). 698 —H —F —CH3 —H —H 1H-NMR (DMSO-d6) Hydrochloride δppm:1.25-1.45 (6H, m), 1.51 (3H, s), 1.65-1.9 (4H, m), 2.0-2.05 (1H, m),2.10 (3H, s), 2.91 (1H, d, J = 13.6 Hz), 3.3-3.45 (1H, m), 3.7-3.8 (1H,m), 3.95-4.05 (1H, m), 6.67 (1H, dd, J = 2.5, 8.5 Hz), 6.74 (1H, dd, J =2.4, 13.5 Hz), 7.08 (1H, dd, J = 8.9, 8.9 Hz), 8.0-8.3 (1H, m),9.75-10.0 (1H, m). 699 —H —H —OCHF2 —H —H 1H-NMR (DMSO-d6) Hydrochlorideδppm: 1.21-1.35 (2H, m), 1.35-1.48 (4H, m), 1.53 (3H, s), 1.63-1.95 (4H,m), 1.98-2.12 (1H, m), 2.94 (1H, d, J = 13.4 Hz), 3.32 (1H, d, J = 13.3Hz), 3.7- 3.8 (1H, m), 3.9-4.05 (1H, m), 6.85-7.26 (5H, m), 8.20 (1H,br), 9.99 (1H, br). 700 —H —H —OCF3 —H —H 1H-NMR (DMSO-d6) Hydrochlorideδppm: 1.25-1.49 (6H, m), 1.49-1.57 (3H, m), 1.65- 1.95 (4H, m),1.95-2.09 (1H, m), 2.96 (1H, d, J = 13.6 Hz), 3.39-3.48 (1H, m),3.71-3.83 (1H, m), 3.98-4.09 (1H, m), 6.98- 7.05 (2H, m), 7.16-7.24 (2H,m), 8.16 (1H, br), 9.65-10.1 (1H, m). 701 —H —Cl —CN —H —H 1H-NMR(DMSO-d6) 1/2 Fumarate δppm: 1.10 (3H, s), 1.15- 1.25 (4H, m), 1.25-1.45(2H, m), 1.45-1.7 (4H, m), 1.85-2.0 (1H, m), 2.76 (1H, d, J = 12.8 Hz),2.85- 3.85 (4H, m), 3.85-3.95 (1H, m), 6.56 (1H, s), 6.94 (1H, dd, J =2.5, 9.1 Hz), 7.09 (1H, d, J = 2.4 Hz), 7.59 (1H, d, J = 9.0 Hz). 702 —H—F —OCF3 —H —H 1H-NMR (DMSO-d6) Hydrochloride δppm: 1.25-1.5 (6H, m),1.52 (3H, s), 1.65-2.1 (5H, m), 2.97 (1H, d, J = 13.8 Hz), 3.54 (1H, d,J = 13.6 Hz), 3.65-3.8 (1H, m), 4.0-4.15 (1H, m), 6.81 (1H, dd, J = 2.2,9.3 Hz), 7.05 (1H, dd, J = 2.9, 14.4 Hz), 7.34 (1H, dd, J = 9.0, 9.0Hz), 8.24 (1H, br), 9.92 (1H, br). 703 —H —F —OCHF2 —H —H 1H-NMR(DMSO-d6) 1/2 Fumarate δppm: 1.10-1.37 (9H, m), 1.44-1.75 (4H, m),1.75-1.90 (1H, m), 2.68 (1H, d, J = 12.4 Hz), 3.15 (1H, d, J = 12.4 Hz),3.25-3.45 (1H, m), 3.7- 3.8 (1H, m), 6.51 (1H, m), 6.67 (1H, d, J = 2.1,9.1Hz), 6.81-7.24 (3H, m) 704 —H —Cl —OCHF2 —H —H 1H-NMR (DMSO-d6) 1/2Fumarate δppm: 1.07-1.36 (9H, m), 1.43-1.58 (1H, m), 1.58- 1.72 (3H, m),1.73-1.89 (1H, m), 2.67 (1H, d, J = 12.2 Hz), 3.0-3.7 (4H, m), 3.7-3.8(1H, m), 6.52 (1H, s), 6.82-7.24 (4H, m). 705 —H —CHF2 —H —H —H 1H-NMR(DMSO-d6) Fumarate δppm: 1.15-1.41 (9H, m), 1.48-1.92 (5H, m), 2.75 (1H,d, J = 12.7 Hz), 2.8- 4.4 (6H, m), 6.46 (1H, d, J = 7.8 Hz), 6.54 (2H,s), 6.62 (1H, s), 6.76 (1H, dd, J = 2.1, 8.5 Hz), 7.0-7.4 (2H, m). 706—H —OCHF2 —F —H —H 1H-NMR (DMSO-d6) 1/2 Fumarate δppm: 0.97-1.36 (9H,m), 1.43-1.73 (4H, m), 1.73- 1.87 (1H, m), 2.67 (1H, d, J = 12.1 Hz),2.95-3.8 (5H, m), 6.52 (1H, s), 6.7- 6.8 (2H, m), 7.0-7.4 (2H, m). 707—H —OCHF2 —Cl —H —H 1H-NMR (DMSO-d6) 1/2 Fumarate δppm: 1.11-1.37 (9H,m), 1.45-1.74 (4H, m), 1.77- 1.91 (1H, m), 2.69 (1H, d, J = 12.3 Hz),2.75-4.2 (5H, m), 6.52 (1H, s), 6.73-6.83 (2H, m), 7.03- 7.43 (2H, m).708 —H —CN —OCHF2 —H —H 1H-NMR (DMSO-d6) 1/2 Fumarate δppm: 1.06-1.21(7H, m), 1.21-1.36 (2H, m), 1.41- 1.70 (4H, m), 1.74-1.89 (1H, m), 2.68(1H, d, J = 12.3 Hz), 2.9-3.75 (4H, m), 3.75-3.85 (1H, m), 6.54 (1H, s),6.99-7.14 (4H, m). 709 —H —OCHF2 —OCHF2 —H —H 1H-NMR (DMSO-d6) 1/2Fumarate δppm: 1.1-1.4 (9H, m), 1.45-1.75 (4H, m), 1.75- 1.9 (1H, m),2.69 (1H, d, J = 12.2 Hz), 2.8-4.3 (5H, m), 6.52 (1H, s), 6.71- 7.38(5H, m). 710 —H —F —OCHF2 —F —H 1H-NMR (DMSO-d6) 1/2 Fumarate δppm:1.08-1.22 (7H, m), 1.25-1.40 (2H, m), 1.42- 1.72 (4H, m), 1.76-1.92 (1H,m), 2.66 (1H, d, J = 12.5 Hz), 2.8-4.35 (5H, m), 6.53 (1H, s), 6.66-6.76 (2H, m), 7.05 (1H, t, J = 72.9 Hz). 711 —H —H —OCH2CHF2 —H —H1H-NMR (DMSO-d6) 2 Hydrochloride δppm: 1.15-1.31 (2H, m), 1.32-1.49 (4H,m), 1.52 (3H, s), 1.62-1.89 (4H m), 1.98-2.08 (1H, m), 2.93 (1H, d, J =13.1 Hz), 3.16 (1H, d, J = 13.2 Hz), 3.7-3.8 (1H, m), 3.80-4.27 (4H, m),6.18-6.50 (1H, m), 6.90 (4H, s), 8.0-8.25 (1H, m), 9.8-10.1 (1H, m). 712—H —F —OCH2CF2 —H —H 1H-NMR (DMSO-d6) Hydrochloride δppm: 1.20-1.46 (6H,m), 1.51 (3H, s), 1.63-1.89 (4H m), 1.92-2.08 (1H, m), 2.91 (1H, d, J =13.4 Hz), 3.29 (1H, d, J = 12.8 Hz), 3.67-3.79 (1H, m), 3.88-4.01 (1H,m), 4.20-4.33 (2H, m), 6.18- 6.52 (1H, m), 6.68 (1H, dd, J = 1.8, 9.1Hz), 6.91 (1H, dd, J = 2.9, 14.7 Hz), 7.10 (1H, dd, J = 9.5, 9.5 Hz),8.0-8.2 (1H, m), 9.75-9.95 (1H, m). 713 —H —CH3 —OCHCF2 —H —H 1H-NMR(DMSO-d6) 1/2 Fumarate δppm: 1.06-1.16 (1H, m), 1.16-1.37 (8H, m), 1.45-1.88 (5H, m), 2.17 (3H, s), 2.69 (1H, d, J = 12.0 Hz), 3.04 (1H, d, J =12.0 Hz), 3.1-3.9 (4H, m), 6.50 (1H, s), 6.71 (1H, dd, J = 3.0, 8.9 Hz),6.75-7.16 (3H, m). 714 —H —OCH3 —OCHCF2 —H —H 1H-NMR (DMSO-d6) 1/2Fumarate δppm: 1.08-1.18 (1H, m), 1.18-1.27 (7H, m), 1.27- 1.38 (1H, m),1.44-1.60 (1H, m), 1.60-1.74 (3H, m), 1.74-1.88 (1H, m), 2.71 (1H, d, J= 12.1 Hz), 3.08 (1H, d, J = 12.2 Hz), 3.15-3.85 (7H, m), 6.40 (1H, dd,J = 2.7, 8.9 Hz), 6.50 (1H, s), 6.57 (1H, d, J = 2.6 Hz), 6.62-7.02 (2H,m). 715 —OCHCF2 —H —H —H —H 1H-NMR (DMSO-d6) — δppm: 0.94-1.14 (1H, m),1.14-1.15 (1H, m), 1.18 (3H, s), 1.26 (3H, s), 1.28-1.43 (2H, m), 1.48(1H, br), 1.61-1.73 (3H, m), 1.76-1.90 (1H, m), 2.49 (1H, d, J = 11.2Hz), 3.05 (1H, d, J = 11.2 Hz), 3.45-3.6 (2H, m), 6.55 (1H, dd, J =70.2, 81.4 Hz), 6.91 (1H, dd, J = 1.4, 8.0 Hz), 6.93-6.99 (1H, m),7.07-7.18 (2H, m)

TABLE 77

Example R⁴ NMR Salt 716

1H-NMR (DMSO-d6) δppm: 1.05-1.25 (2H, m), 1.35-1.45 (1H, m), 1.47 (3H,s), 1.50 (3H, s), 1.6-2.05 (5H, m), 2.15 (3H, d, J = 0.7 Hz), 2.70 (1H,d, J = 12.8 Hz), 3.20 (1H, d, J = 12.9 Hz), 3.25-3.4 (1H, m), 3.8-3.9(1H, m), 6.77 (1H, d, J = 3.2 Hz), 7.09 (1H, dd, J = 1.0, 3.3 Hz),7.9-8.1 (1H, m), 9.6- 9.75 (1H, m). — 717

1H-NMR (DMSO-d6) δppm: 0.95-1.15 (2H, m), 1.3-1.45 (1H, m), 1.52 (3H,s), 1.56 (3H, s), 1.6-1.7 (1H, m), 1.7-2.1 (4H, m), 2.87 (1H, d, J =12.8 Hz), 3.36 (1H, d, J = 13.1 Hz), 3.65-3.75 (1H, m), 4.1-4.2 (1H, m),7.06 (1H, s), 7.35-7.45 (2H, m), 7.9- 8.0 (2H, m), 8.0-8.15 (1H, m),9.6-9.8 (1H, m). Hydrochloride

TABLE 78

Example R⁴ NMR Salt 718

1H-NMR (CDCl3) δppm: 1.08-1.15 (18H, m), 1.19-1.34 (12H, m), 1.35-1.48(2H, m), 1.64-1.85 (4H, m), 2.82 (1H, d, J = 11.6 Hz), 3.04 (1H, d, J =11.7 Hz), 3.45-3.55 (1H, m), 3.7-3.8 (1H, m), 6.95 (1H, d, J = 2.2 Hz),7.03 (1H, dd, J = 2.5, 8.8 Hz), 7.10 (1H, d, J = 2.4 Hz), 7.23 (1H, d, J= 2.5, 9.1 Hz), 7.51 (1H, d, J = 8.8 Hz), 7.55 (1H, d, J = 9.1 Hz). —719

1H-NMR (CDCl3) δppm: 1.13 (18H, d, J = 7.3 Hz), 1.18-1.36 (12H, m),1.36-1.65 (2H, m), 1.65-1.87 (4H, m), 2.83 (1H, d, J = 11.9 Hz), 3.12(1H, d, J = 11.9 Hz), 3.45-3.55 (1H, m), 3.75-3.85 (1H, m), 6.82 (1H, d,J = 2.3 Hz), 6.86 (1H, dd, J = 2.4, 8.7 Hz), 7.02 (1H, d, J = 2.3 Hz),7.10 (1H, dd, J = 2.4, 9.0 Hz), 7.53 (1H, d, J = 8.7 Hz), 7.59 (1H, d, J= 9.0 Hz). — 720

1H-NMR (CDCl3) δppm: 1.04-1.12 (18H, m), 1.12-1.32 (12H, m), 1.32-1.64(2H, m), 1.65-1.86 (4H, m), 2.82 (1H, d, J = 11.8 Hz), 3.08 (1H, d, J =11.8 Hz), 3.47-3.53 (1H, m), 3.73-3.81 (1H, m), 3.88 (3H, s), 5.17 (1H,d, J = 11.0 Hz), 5.24 (1H, d, J = 11.0 Hz), 6.94 (1H, d, J = 2.5 Hz),7.16 (1H, d, J = 9.0 Hz), 7.31 (1H, dd, J = 2.5, 9.4 Hz), 7.58 (1H, d, J= 9.0 Hz), 8.12 (1H, d, J = 9.4 Hz). — 721

1H-NMR (CDCl3) δppm: 1.14 (18H, d, J = 6.7 Hz), 1.19-1.33 (13H, m),1.33-1.65 (1H, m), 1.65-1.84 (4H, m), 2.83 (1H, d, J = 11.6 Hz), 3.04(1H, d, J = 11.6 Hz), 3.5-3.6 (1H, m), 3.7-3.8 (1H, m), 3.87 (3H, s),4.93 (2H, d, J = 0.9 Hz), 6.96 (1H, s), 6.99 (1H, d, J = 2.2 Hz), 7.21(1H, dd, J =2.4, 9.0 Hz), 7.59 (1H, d, J = 9.0 Hz), 7.77 (1H, s). —

TABLE 79

Example R⁴ NMR Salt 722

1H-NMR (CDCl3) δppm: 1.14-1.51 (11H, m), 1.65-1.85 (4H, m), 2.83 (1H, d,J = 11.7 Hz), 3.05 (1H, d, J = 11.8 Hz), 3.52-3.57 (1H, m), 3.69-3.79(1H, m), 6.97 (1H, d, J = 2.3 Hz), 6.99-7.06 (2H, m), 7.22-7.28 (1H, m),7.52-7.58 (2H, m). — 723

1H-NMR (CDCl3) δppm: 1.18-1.36 (9H, m), 1.35-1.51 (2H, m), 1.66-1.86(4H, m), 2.84 (1H, d, J = 11.9 Hz), 3.13 (1H, d, J = 12.0 Hz), 3.45-3.55(1H, m), 3.75-3.85 (1H, m), 6.8-6.85 (2H, m), 6.94 (1H, d, J = 2.4 Hz),7.10 (1H, d, J = 2.4, 9.1 Hz), 7.57 (1H, d, J = 8.7 Hz), 7.60 (1H, d, J= 9.0 Hz). — 724

1H-NMR (DMSO-d6) δppm: 1.1-1.2 (1H, m), 1.2-1.4 (8H, m), 1.5-1.9 (5H,m), 2.86 (1H, d. J = 12.2 Hz), 3.20 (1H, d, J = 12.5 Hz), 3.58 (1H, br),3.85 (3H, s), 3.9- 4.0 (1H, m), 4.85 (2H, s), 6.54 (2H, s), 7.05 (1H, d,J = 2.4 Hz), 7.28 (1H, d, J = 9.1 Hz), 7.39 (1H, dd, J = 2.5, 9.5 Hz).7.66 (1H, d, J = 9.0H), 7.97 (1H, d, J = 9.4 Hz). Fumarate 725

1H-NMR (CDCl3) δppm: 0.97 (1H, br), 1.15-1.35 (8H, m), 1.35-1.5 (2H, m),1.65- 1.85 (4H, m), 2.42 (1H, t, J = 6.5 Hz), 2.82 (1H, d, J = 11.8 Hz),3.05 (1H, d, J = 11.7H), 3.45-3.55 (1H, m), 3.7-3.8 (1H, m), 3.94 (3H,s), 4.79 (2H, d, J = 5.9 Hz), 6.98 (1H, d, J = 2.4 Hz), 7.02 (1H, s),7.21-7.28 (1H, m), 7.54 (1H, s). 7.60 (1H, d, J = 9.0 Hz). —

TABLE 80 absolute configuration

Example R⁴ NMR Salt 726

1H-NMR (DMSO-d6) δ ppm: 0.9-1.05 (1H, m), 1.05-1.2 (1H, m), 1.3-1.46(1H, m), 1.52 (3H, s), 1.55-1.85 (4H, m), 1.65-1.85 (2H, m), 1.85-2.05(2H, m), 2.73 (1H, d, J = 12.5 Hz), 3.25-3.6 (2H, m), 3.94 (3H, s),4.15-4.3 (1H, m), 6.88 (1H, d, J = 8.2 Hz), 7.06 (1H, d, J = 8.0 Hz),7.5-7.55 (1H, m), 7.55-7.6 (1H, m), 7.96 (1H, br), 8.16 (1H, dd, J =1.0, 8.3 Hz), 8.24 (1H, d, J = 8.1 Hz), 9.4-9.6 (1H, m). Hydrochloride727

1H-NMR (DMSO-d6) δ ppm: 0.85-1.0 (1H, m), 1.0-1.15 (1H, m), 1.3-1.4 (1H,m), 1.5- 1.65 (7H, m), 1.65-1.85 (2H, m), 1.86-2.1 (2H, m), 2.59 (3H,s), 2.76 (1H, d, J = 12.5 Hz), 3.3-3.45 (1H, m), 3.51 (1H, d, J = 12.5Hz), 4.15-4.3 (1H, m), 7.02 (1H, d, J = 7.5 Hz), 7.28 (1H, d, J = 7.4Hz), 7.5-7.65 (2H, m), 7.95-8.15 (2H, m), 8.25-8.35 (1H, m), 9.6-9.8(1H, m). Hydrochloride 728

1H-NMR (DMSO-d6) δ ppm: 1.23-1.54 (6H, m), 1.58 (3H, s), 1.64-2.02 (4H,m), 2.02- 2.15 (1H, m), 3.07 (1H, d. J = 13.4 Hz), 3.50 (1H, d, J = 13.4Hz), 3 75-3.9 (1H, m), 3.9-4.53 (2H, m), 7.18 (1H, d, J = 22 Hz),7.22-7.32 (1H, m), 7.32-7.46 (2H, m), 7.65- 7.82 (3H, m), 8.26 (1H, br),10.02 (1H, br). 2 Hydrochloride 729

1H-NMR (CDCl3) δ ppm: 0.83-0.99 (1H, m), 1.021.13 (1H, m), 1.27 (3H, s),1.32- 1.42 (2H, m), 1.46 (3H, s), 1.54-1.71 (2H, m), 1.71-1.81 (1H, m),1.85-1.99 (1H, m), 2.69 (1H, d, J = 11.1 Hz), 3.3-3.45 (2H, m),3.75-3.85 (1H, m), 7,15 (1H, s), 7.5-7.55 (2H, m), 7.6-7.7 (2H, m),7.7-7.8 (1H, m), 8.3-8.4 (1H, m), 8.55-8.65 (1H, m), 8.65- 8.75 (1H, m).— 730

1H-NMR (CDCl3) δ ppm: 0.9-1.65 (11H, m), 1.65-1.9 (4H, m), 2.84 (1H, d,J = 12.0 Hz), 3.13 (1H, d, J = 11.9 Hz), 3.50 (1H, bs), 3.75-3.35 (1H,m), 3.89 (3H, s), 6.89 (1H, dd, J = 2.5, 8.8 Hz), 6.92 (1H, d, J = 2.4Hz), 6.97 (1H, d, J = 2.4 Hz), 7.11 (1H, dd, J = 2.5, 9.0 Hz), 7.57 (1H,d, J = 8.6 Hz), 7.60 (1H, J = 9.0 Hz). — 731

1H-NMR (DMSO-d6) δ ppm: 1.3-1.5 (6H, m), 1.55 (3H, s), 1.65-2,05 (5H,m), 3.08 (1H, d, J = 13.6 Hz), 3.62 (1H, d, J = 13.6 Hz), 3.8-3.9 (1H,m), 4.2-4.3 (1H, m), 7.32 (1H, d, J = 2.1 Hz), 7.50 (1H, dd, J = 1.6,8,4 Hz), 7.63 (1H, dd, J = 2.5, 9.2 Hz), 7.85-8.0 (2H, rn), 8.11-8.2(1H, m), 8.26 (1H, s), 9.6-9.75 (1H, m). Hydrochloride 732

1H-NMR (DMSO-d6) δ ppm: 1.32-1.54 (6H, m), 1.57 (3H, s), 1.66-2.13 (5H,m), 3.10 (1H, d, J = 13.9 Hz), 3.72 (1H, d, J = 13.7 Hz), 3.75-3.9 (1H,m), 4.25-4.35 (1H, m), 7.29 (1H, d, J = 2.2 Hz), 7.5-7.65 (2H, m), 7.81(1H, d, J = 8.6 Hz), 7.91 (1H, d, J = 9.2 Hz), 8.15-6.45 (2H, m), 9.92(1H, br). Hydrochloride 733

1H-NMR (DMSO) δ ppm: 1.0-1.35 (9H, m), 1.4-1.6 (2H, m), 1.6-1.7 (3H, m),1.8-1.95 (1H, m), 2.72 (1H, d, J = 12.3 Hz), 3.12 (1H, d, J = 11.1 Hz),3.3-3.4 (1H, m), 3 8- 3.9 (1H, m), 3.92 (3H, s), 7.09 (1H, d, J = 1.8Hz), 7.39 (1H, d, J = 9.2 Hz), 7.49 (1H, dd, J = 2.4, 9.5 Hz), 7.71 (1H,d, J = 9.0 Hz), 7.89 (1H, d, J = 9.4 Hz). — 734

1H-NMR (CDCl3) δ ppm: 1.00 (1H, br), 1.19-1.37 (8H, m), 1-38-1.51 (2H,m), 1.57- 1.79 (3H, m), 1.79-1.93 (1H, m), 2.90 (1H, d, J = 11.8 Hz),3.18 (1H, d, J = 11.9 Hz), 3.53 (1H, br), 3.8-3.9 (1H, m), 7,05 (1H, d,J = 2.1 Hz), 7.3-7.45 (3H, m), 7.8-7.95 (3H, m), 8.15 (1H, s), 8.25 (1H,s). — 735

1H-NMR (DMSO-d6) δ ppm: 1.15-1.25 (1H, m), 1.25-1.4 (8H, m), 1.5-1.95(5H, m), 2.88 (1H, d, J = 12.6 Hz), 3.31 (1H, d, J = 12.4 Hz), 3.54 (1H,br), 3.95-4.05 (1H, m), 6.54 (2H, s), 7.13 (1H, d, J = 2.1 Hz), 7.34(1H, dd. J = 2.2, 8.7 Hz), 7.44 (1H, dd, J = 2.4. 9.2 Hz), 7.87-7.76(2H, m), 7.81 (1H, d, J = 2.1 Hz). Fumarate 736

1H-NMR (CDCl3) δ ppm: 1.09 (1H, br), 1.16-1.35 (8H, m), 1.35-1.5 (2H,m), 1.65- 1.85 (4H, m), 2.50 (3H, s), 2.82 (1H, d, J = 11.6 Hz), 3.07(1H, d, J = 11.8 Hz), 3.45-3.55 (1H, m), 3.7-3.8 (1H, m), 3.90 (3H, s),6.96 (1H, d, J = 2.5 Hz), 7.18 (1H, d, J = 9.0 Hz), 7.30 (1H, dd, J =2.6, 9.4 Hz), 7.51 (1H, d, J = 9.0 Hz), 7.81 (1H, d, J = 9.3 Hz). — 737

1H-NMR (DMSO-d6) δ ppm: 1.06-1.19 (1H, m), 1.19-1.39 (8H, m), 1.47-1.80(4H, m), 1.80-1.96 (1H, m), 2.83 (1H, d, J = 12.2 Hz), 2.9-4.4 (5H, m),6.51 (1H, s), 7.05-7.45 (4H, m), 7.49 (1H, d, J = 2.4 Hz), 7.7-7.8 (2H,m). ½ Fumarate 738

1H-NMR (DMSO-d6) δ ppm: 1.23-1.54 (6H, m), 1.80 (3H, s), 1.66-2.08 (4H,m), 2.06- 2.20 (1H, m), 3.07 (1H, d, J = 13.4 Hz), 3.45 (1H, d, J = 13.9Hz), 3.75-3.9 (1H, m), 5.95 (3H, s), 4.1-4.2 (1H, m), 4.77 (1H, br),7.25 (1H, d. J = 2.2 H), 7.46 (1H, s), 7.58 (1H, dd, J = 2.4, 9.2 Hz),7.81 (1H, d, J = 9.2 Hz), 8.23 (1H, s), 8.25-8.4 (1H, m), 10.18 (1H,br). 2 Hydrochloride 739

1H-NMR (DMSO-d6) δ ppm: 1.27-1.50 (6H, m), 1.58 (3H, s), 1.65-2.13 (5H,m), 3.06 (1H, d, J = 13.8 Hz), 3.58 (1H, d, J = 13.6 Hz), 3.73-3.87 (1H,m), 4.14-4.26 (1H, m), 7.05 (1H, d, J = 1.8 Hz), 7.28-7.38 (2H, m),7.43-7.52 (1H, m), 7.75 (1H, d, J = 8.5 Hz), 7.84 (1H, d, J = 8.2 Hz),8.15-8.4 (1H, m), 9.9-10.1 (1H, m). Hydrochloride 740

1H-NMR (DMSO-d6) δ ppm: 1.28-1.50 (6H, m), 1.57 (3H, s), 1.68-2.00 (4H,m), 2.00- 2.18 (1H, m), 3.08 (1H, d, J = 13.5 Hz), 3.56 (1H, d, J = 13.5Hz), 3.75-3.9 (1H, m), 3.95-4.1 (1H, m), 7.23 (1H, d, J = 2.0 Hz),7.38-7.45 (1H, m), 7.45-7.64 (1H, m), 7.65 (1H, d, J = 2.4 Hz), 7.78(1H, d, J = 8.1 Hz), 7.97 (1H, d, J = 8.4 Hz), 8.1-8.35 (1H, m),9.6-10.1 (1H, m). Hydrochloride 741

1H-NMR (DMSO-d6) δ ppm: 1.06-1.17 (1H, m), 1.17-1.39 (8H, m), 1.49-1.70(4H, m), 1.79-1.92 (1H, m), 2.82 (1H, d, J = 12.1 Hz), 2.9-4.2 (5H, m),4.30-4.41 (2H, m), 8.27-6.59 (2H, m), 7.06 (1H, d, J = 2.1 Hz), 7.10(1H, dd, J = 2.6, 8.9 Hz), 7.26 (1H, d, J = 2.5 Hz), 7.36 (1H, dd, J =2.4, 9.2 Hz), 7.60-7.68 (2H, m). ½ Fumarate

TABLE 81 absolute configuration

Example R⁴ NMR Salt 742

1H-NMR (DMSO-d6) δ ppm: 1.0-1.15 (2H, m), 1.3-1.45 (1H, m), 1.48 (3H,s), 1.50 (3H, s), 1.55-1.85 (1H, m), 1.65-1.8 (2H, m), 1.8-2.0 (2H, m),2.25-2.35 (1H, m), 2.4-2.5 (1H, m), 2.6-2.75 (2H. m), 2.95-3.1 (2H. m),3.21 (3H. s), 3.3-3 5 (1H, m), 3.78 (3H, s), 3.85-3.95 (1H, m), 6.78(1H, d, J = 8.9 Hz), 6.93 (1H. d, J = 8.9 Hz), 7.97 1H, br), 9.59 (1H,br). Hydrochloride 743

1H-NMR (DMSO-d6) δ ppm: 1.08-1.37 (9H, m), 1.42 (6H, s), 1.48-1.83 (5H,m), 2.74 (1H. d, J = 12.2 Hz), 2.94 (1H, d. J = 12.3 Hz), 3.51 (1H, br),3.6-3.75 (1H, m), 4.73 (2H, 5), 6.53 (2H. s), 6.57 (1H. d. J = 2.6 Hz),6.65 (1H, d. J = 8.3 Hz), 6.75 (1H, dd, J = 2.8, 9.0 Hz). Fumarate

TABLE 82 absolute configuration

Example R⁴ NMR Salt 744

1H-NMR (CDCl3) δ ppm: 0.94-1.08 (3H, m), 1.20 (3H. s), 1.34 (3H, s),1.36-1.44 (2H, m), 1.49-1.79 (3H, m), 1.81-1.94 (1H. m), 2.55-2.65 (4H,m), 3.15 (1H, d, J = 11.2 Hz), 3.4-3.5 (1H. m), 3.65-3.7 (1H, m), 6.74(1H. dd, J = 0.6, 7.6 Hz), 7.05 (1H, s), 7.13 (1H, dd, J = 7.8; 7.8 Hz),7.38 (1H, d, J = 8.0 Hz). — 745

1H-NMR (DMSO-d6) δ ppm: 1.1-1.2 (1H, m), 1.2-1.4 (8H, m), 1.45-1.75 (4H,m), 1.75-1.9 (1H, m), 2.47 (3H, d, J = 1.2 Hz), 2.6-2.7 (6H, m), 6.49(1H. s), 6.90 (1H, s), 6.99 (1H, dd, J = 2.3, 8.8 Hz), 7.25 (1H, d, J =2.1 Hz), 7.48 (1H. d, J = 8.8 Hz). ½ Fumarate 746

1H-NMR (DMSO-d6) δ ppm: 1.1-1.4 (9H, m), 1.5-1.95 (5H, m), 2.31 (3H, d,J = 1.2 Hz), 2.6-5.0 (7H, m), 6.52 (2H, s), 7.01 (1H, d, J = 1.2 Hz),7.11 (1H, dd, J = 2.3, 8.9 Hz), 7.34 (1H, d, J = 2.2 Hz), 7.55 (1H, d, J= 8.8 Hz). ½ Fumarate 747

1H-NMR (DMSO-d6) δ ppm: 0.93-1.10 (2H, m), 1.28-1.42 (1H, m), 1.51-1.66(7H, m), 1.70-2.00 (3H, m), 2.00-2.18 (1H, m), 2.69 (3H, s), 2.80 (1H,d, J = 12.5 Hz), 3.2-3.3 (1H. m), 3.48 (1H, d, J = 12.6 Hz), 3.85-3.95(1H, m), 7.02 (1H, d. J = 7.5 Hz), 7.26 (1H, d, J = 7.8. 7.8 Hz), 7.36(1H, d, J = 0.6 Hz), 7.69 (1H, d, J = 7.6 Hz), 7.95-8.15 (1H, m),9.95-10.1 (1H, m). Hydrochloride 748

1H-NMR (CDCl3) δ ppm: 0.92-1.08 (3H, m), 1.20 (3H, s), 1.32-1.43 (5H,m), 1.45- 1.78 (3H, m), 1.81-1.94 (1H, m), 2.67 (1H, d, J = 11.1 Hz),3.14 (1H, d, J = 11.1 Hz), 3.33-3.41 (1H, m), 3.63-3.70 (1H, m), 6.71(1H, dd, J = 4.1, 8.4 Hz), 6.92 (1H, dd. J = 8.9. 8.9 Hz), 7.41 (1H, d,J = 5.4 Hz), 7.46 (1H, dd, J = 3.7, 5.4 Hz). — 749

1H-NMR (CDCl3) δ ppm: 0.92-1.08 (3H, m), 1.20 (3H, s), 1.29-1.42 (5H,m), 1.45- 1.78 (3H, m), 1.82-1.96 (1H, m), 2.61 (1H, d, J = 11.2 Hz),3.15 (1H, d, J = 11.1 Hz), 3.42-3.50 (1H, m), 3.64-3.71 (1H, m), 6.74(1H, d, J = 8.2 Hz), 7.21 (1H, d, J = 8.2 Hz), 7.43 (1H, d, J = 5.5 Hz),7.47 (1H, d, J = 5.5 Hz). — 750

1H-NMR (CDCl3) δ ppm: 0.9-1.1 (2H, m), 1.20 (3H, s), 1.3-1.45 (5H, m),1.45-1.8 (4H, m), 1.8-1.95 (1H, m), 2.56 (1H, d. J = 11.1 Hz), 3.14 (1H,d. J = 11.1 Hz), 3.3-3.4 (1H, m), 3.5-3.7 (1H, m), 3.96 (3H, s), 6.66(1H, d, J = 8.2 Hz), 6.74 (1H, d, J = 8.2 Hz), 7.39 (1H, d, J = 5 4 Hz),7.45 (1H, d, J = 5.4 Hz). — 751

1H-NMR (CDCl3) δ ppm: 0.95-1.1 (2H, m), 1.22 (3H, s), 1.3-1.45 (5H, m),1.45-1.85 (4H, m), 1.85-2.0 (1H, m), 2.65 (1H, d, J = 11.2 Hz), 3.17(1H, d, J = 11.2 Hz), 3.45-3.55 (1H, m), 3.7-3.8 (1H, m), 3.96 (3H, s),6.77-6.82 (1H, m), 7.33 (1H, dd, J = 7.9, 7.9 Hz), 7.45 (1H, d, J = 8.1Hz), 8.14 (1H, d, J = 0.5 Hz). — 752

1H-NMR (CDCl3) δ ppm: 0.93 (1H, br), 1.16-1.33 (8H, m), 1.33-1.49 (2H,m), 1.64- 1.85 (4H, m), 2.80 (1H, d, J = 11.6 Hz), 2.97 (1H, d, J = 11.7Hz), 3.48 (1H, br), 3.6-3.7 (1H, m), 7.04 (1H, d, J = 2.1 Hz), 7.10 (1H,d, J = 2.2 Hz), 7.20 (1H, d, J = 5.4 Hz), 7.41 (1H, d. J = 5.5 Hz). —753

1H-NMR (DMSO-d6) δ ppm: 0.94-1.14 (2H, m), 1.29-1.44 (1H, m), 1.51)3H,s), 1.53 (3H, s), 1.58-2.07 (5H, m), 2.84 (1H, d, J = 12.9 Hz), 3.41(1H, d, J = 13.0 Hz), 3.6-3.7 (1H, m), 4.15-4.25 (1H, m), 7.11 (1H, dd,J = 6.5, 12.6 Hz), 7.77 (1H, dd, J = 3.8, 5.4 Hz), 7.84 (1H, d, J = 5.4Hz), 8.04 (1H. br) 9.81 (1H, br). Hydrochloride 754

1H-NMR (DMSO-d6) δ ppm: 1.38-1.57 (5H, m), 1.64 (3H, s), 1.70-2.02 (4H,m), 2.03- 2.14 (1H, m), 2.37-2.54 (1H, m) , 3.55 (1H, d, J = 15.0 Hz),3.9-4.0 (1H, m), 4.23 (1H, d, J = 15.3Hz), 4.6-4.75 {1H, m7 27 (1H. d. J= 7.2 Hz), 7.67 (1H d, J = 5.7 Hz), 8.45-8.6 (2H, m), 8.88 (1H, br),10.33 (1H, m), 14.95 (1H, br). 2 Hydrochloride 755

1H-NMR (DMSO-d6) δ ppm: 1.0-1.19 (2H, m), 1.31-1.46 (1H, m), 1.51 (3H,s), 1.52 (3H, s), 1.80-1.89 (3H, m), 1.93-2.08 (2H, m), 3.00 (1H, d, J =12.9 Hz), 3.46 (1H, d, J = 13.0 Hz), 3.90-4.01 (1H, rn), 3.95-4.08 (1H,m), 6.96 (1H, dd, J = 2.1, 11.0 Hz), 7.41 (1H, dd, J = 2.2, 9.1 Hz),7.46 (1H, d, J = 5.4 Hz), 7.86 (1H, d, J = 5.4 Hz), 8.16 (1H. br), 9.78(1H, br). Hydrochloride

TABLE 83 absolute configuration

Example R⁴ NMR Salt 756

1H-NMR (CDCl3) δ ppm: 1.02-1.17 (3H, m), 1.20 ( 3H, s), 1.31 ( 3H, s ),1.34-1.46 (2H, m), 1 47-1.79 (3H, m). 1.81-1.95 (1H, m), 2.45 (3H, d, J= 1.0 Hz), 2.80 (1H, d, J = 11.5 Hz), 3.05 (1H, d, J = 11.5 Hz),3.55-3.65 (2H, m), 6.39 (1H, dd, J = 1.0, 1.0 Hz), 6.56 (1H, dd, J =0.8, 7.7 Hz), 6.95-7.05 (1H, m), 7.06 (1H, dd, J = 7.9, 7.9 Hz). — 757

1H-NMR (DMSO-d6) δ ppm: 1.17-1.37 (2H, m), 1.37-1.52 (4H, m), 1.58 (3H,s), 1.61- 1.73 (1H, m), 1.73-1.99 (3H, m), 2.00-2.15 (1H, m), 2.37 (3H,d, J = 0.9 Hz), 3.00 (1H, d, J = 13.3 Hz), 3.28 (1H, d, J = 13.2 Hz),3.7-3.85 (1H, m), 3.95-4.1 (1H, m), 4.92 (1H, br), 6.40 (1H, d, J = 0.8Hz), 6.89 (1H, dd, J = 2.1, 8.8 Hz), 7.05 (1H, d, J = 1.5 Hz), 7.33 (1H,d, J = 8.5 Hz), 8.15-8.35 (1H, m), 10.0-10.2 (1H, m). 2 Hydrochloride758

1H-NMR (DMSO-d6) δ ppm: 1.01-1.19 (2H, m), 1.33-1.44 (1H, m), 1.48 (3H,s), 1.51 (3H, s), 1.59-2.07 (5H, m), 3.01 (1H, d, J = 13.0 Hz}, 3.28(1H, d, J = 13.1 Hz), 3.75-3.9 (1H, m), 4.0-4.15 (1H, m), 6.83 (1H, dd,J = 5.9, 13.5 Hz ), 7.36 (1H, dd, J = 2.6, 2.6 Hz), 8.0-8.2 (2H, m),9.7-9.9 (1H m). Hydrochloride 759

1H-NMR (DMSO-d6) δ ppm: 1.0-1.2 (2H, m), 1.34-1.44 (1H, m), 1.50 (3H,s), 1.53 (3H, s), 1.60-2.06 (5H, m), 3.05 (1H, d, J = 12.8 Hz), 3.27(1H, d, J = 13.0 Hz), 3.84 (3H, s), 3.86-4.00 (2H, m), 6.66 (1H, d, J =8.5 Hz), 6.75 (1H, d, J = 8.5 Hz), 8.93 (1H, J = 2.2 Hz), 7.92 (1H, d, J= 2.2 Hz), 8.0-6.25 (1H, m), 9.55-9.8 (1H, m)._ Hydrochloride 760

1H-NMR (CDCl3) δ ppm: 0.99-1.24 (5H, m), 1.28 (3H, s), 1.33-1.47 (2H,m), 1.48- 1.84 (5H, m), 2.77-2.50 (2H, m), 3.45-3.55 (1H, m), 3.55-3.65(1H, m), 4.01 (3H, s), 6.51 (1H, d, J = 2.0 Hz), 6.58 (1H, d, J = 2.1 Hz), 6.63 (1H, d. J = 2.1 Hz ), 7.53 (1H, d, J = 2.0 Hz). — 761

1H-NMR (DMSO-d6) δ ppm: 1.05-1.25 (2H. m), 1.35-1.45 (1H, m), 1.48 (3H,s), 1.52 (3H, s) 1.6-2.05 (5H, m), 3.13 (1H, d, J = 13.2 Hz) 3.28 (1H,d, J = 13.5 Hz), 3.9-4.0 (1H, m), 4.0-4.1 (1H, m ), 6.63 (1H, dd, J =2.1, 12.3 Hz), 7.09 (1H, dd, J = 1.3, 8.7 Hz), 7.22 (1H, dd, J = 0.7,2.2 Hz), 7.96 (1H, d, J = 2.3 Hz), 8.0-8.2 (1H, m), (9.6-9.9 (1H, m).Hydrochloride 762

1H-NMR (DMSO-d6) δ ppm: 1.16-1.34 (2H, m), 1,35-1.45 (1H, m), 1.47 (3H,s), 1.54 (3H, s), 1.88-1.39 (3H, m), 1.92-2.11 (2H, m), 3.25 (1H, d, J =13.6 Hz), 3.45 (1H, d, J = 13.4 Hz), 3.83-4.02 (1H, m), 4.20-4.38 (1H,m), 6.68 (1H, dd, J = 2.0, 12.2 Hz), 6.87-7.05 (2H, m), 8.02 (1H, d, J =2.1 Hz), 8.24 (1H, br), 9.7-10.0 (1H, m). Hydrochloride 763

1H-NMR (DMSO-d6) δ ppm: 1.27-1.47 (6H, m), 1.53 (3H, s), 1.61-1.96 (4H,m), 1.97- 2.09 (1H, m), 3.00 (1H, d. J = 13.6 Hz), 3.45 (1H, d, J = 13.5Hz), 3.71-3.81 (1H, m), 4.05-4.15 (1H, m), 6.81-6.93 (2H, m), 6.98- 7.04(1H, m), 7.83 (1H, d, J = 2.2 Hz), 8.1- 8.3 (1H, m), 9.8-10.0 (1H, m).Hydrochloride 764

1H-NMR (DMSO-d6) δ ppm: 1.18-1.46 (6H, m), 1.53 (3H, s), 1.62-1.93 (4H,m), 1.95- 2.13 (1H, m), 3.00 (1H, d, J = 13.3 Hz), 3.30 (1H, d, J = 13.2Hz), 3.7-3.85 (1H, m), 3.95- 4.1 (1H, m ), 4.83 (1H, br) 6.91 (1H, dd, J= 2.2, 3.0 Hz), (1H, d, J = 2.1 Hz), 7.01 (1H. dd, J = 2.1, 14.2 Hz ),7.99 (1H, d, J = 2.1 Hz), 6.12 (1H, br), 9.86 (1H, br). 2 Hydrochloride765

1H-NMR (DMSO-d6) δ ppm: 1.21-1.37 (2H, m), 1.37-1.47 (4H, m), 1.52 (3H,s), 1-62- 1.90 (4H, m), 1.95-2.08 (1H, m), 3.02 (1H, d, J = 13.2 Hz),3.29 (1H, d, J = 13.2 Hz), 3.75-3.9 (1H, m), 3.95-4.1 (1H, m), 8.92 (1H,d, J = 2.2 Hz), 7.12 (1H, d, J = 2.2 Hz), 7.16 (1H, d, J = 2.2 Hz), 8.01(1H, d, J = 2.1 Hz}, 8.06 (1H, br), 9.74 (1H, br) Hydrochloride 766

1H-NMR (DMSO-d6) δ ppm: 1.19-1.36 (2H, m), 1.38-1.48 (4H, m), 1.52 (3H,s), 1.62- 1.89 (4H, m), 1.93-2.06 (1H, m), 3.03 (1H, d, J = 13.3 Hz),3.25-3.4 (1H, m), 3.75-3.9 (1H, m), 4.0-4.1 (1H, m), 7.22 (1H, d, J =2.4 Hz), 7.37 (1H, dd, J = 2.5, 9.3 Hz ), 7.62 (1H, d, J = 9.2 Hz), 7.95(1H, d, J = 0.7 Hz), 8.06 (1H, br), 9.64 (1H, br). Hydrochloride 767

1H-NMR (DMSO-d6) δ ppm: 1.15-1.29 (8H, m), 1.29-1.40 (2H, m), 1.46-1.80(4H, m), 1.80-1.96 (1H, m), 2.83 (1H, d, J = 12.8 Hz), 2.9-3.85 (4H, m),3.9-4.0 (1H, m), 6.55 (2H, s), 7.09 (1H, s), 7.13 (1H dd, J = 2.1, 8.9Hz), 7.56 (1H, d, J = 6.9 Hz), 7.89 (1H, d, J = 0.6 Hz). Fumarate 768

1H-NMR (DMSO-d6) δ ppm: 0.85-1.1 (2H, m), 1.2-1.35 (7H, m), 1.4-1.8 (4H,m), 1.86-2.05 (1H, m), 2.78 (1H, d, J = 11.8 Hz), 2.85-4.5 (5H, m ), 5.5(1H, s), 6.58 (1H, d, J = 8.6 Hz), 7.0-7.4 (3H, m), 7.99 (1H, d, J = 2.2Hz). ½ Fumarate

TABLE 84 absolute configuration

Example R⁴ NMR Salt 769

1H-NMR (CDCl3) δ ppm: 1.11-1.18 (20H, m), 1.22 (3H, s), 1-26-1.36 (4H,m), 1.37- 1.49 (2H, m), 1.64-1.87 (7H, m), 2.82 (1H, d, J = 11.8 Hz),3.02 (1H, d, J = 11.8 Hz), 3.45-3.55 (1H, m), 3.6-3.7 (1H, m), 6.82 (1H,s), 6.88 (1H, dd, J = 2.0, 8.9 Hz), 7.54 (1H, d, J = 8.8 Hz), 8.04 (1H,d, J = 0.8 Hz). — 770

1H-NMR (CDCl3) δ ppm: 1.11-1.19 (19H, m), 1.21 (3H, s), 1.23-1.31 (2H,m), 1.35 (3H, s), 1.37-1.46 (2H, m) 1.62-1.85 (6H, m), 1.95-2.04 (1H,m), 3.03 (1H, d, J = 11.9 Hz), 3.09 (1H, d, J = 12.0 Hz}, 3.55-3.65 (1H,m ), 3.8-3.9 (1H, m), 6.41 (1H, d, J = 7.5 Hz), 7.05 (1H, d, J = 6.4Hz), 7.16 (1H, dd, J = 7.6, 8.3 Hz), 8.26 (1H, d, J = 0.8 Hz). — 771

1H-NMR (CDCl3) δ ppm: 1.17-1.23 (21H, m), 1.25-1.33 (5H, m), 1.33-1.50(3H, m), 1.62-1.90 (4H, m), 1.93-2.05 (3H, m), 2.82 (1H, d, J = 11.8Hz), 3.00 (1H, d, J = 11.8 Hz ), 3.45-3.50 (1H, m), 3.55-3.65 (1H, m),6.88-6.95 (2H, m), 7.28 (1H, s), 7.41- 7.48 (1H, m). — 772

1H-NMR (CDCl3) δ ppm: 0.93-1.17 (21H, m), 1.19 (3H, s), 1.23-1.44 (5H,m), 1.58- 1.76 (8H, m), 1.78-1.93 (1H, m), 2.67 (1H, d, J = 11.2 Hz),3.09 (1H, d, J = 11.2 Hz), 3.5- 3.6 (1H, m), 3.6-3.7 (1H, m), 6.39 (1H,dd, J = 3.4, 8.3 Hz), 6.65 (1H, dd, J = 3.2, 3.2 Hz), 6.72 (1H, d, J =8.2, 12.7 Hz), 7.25 (1H, d, J = 3.2 Hz). — 773

1H-NMR (CDCl3) δ ppm: 1.12-1.29 (27H, m), 1.30-1.48 (2H, m), 1.62-1.82(4H, m), 1.93-2.07 (3H, m), 2.78 (1H d, J = 11.6 Hz), 2.93 (1H, d, J =11.8 Hz), 3.45-3.55 (1H, m), 3.6-3.7 (1H, m), 6.92 (1H, d, J = 2.4 Hz),7.07 (1H, dd, J = 2.5, 9.4 Hz), 7.24 (1H, s), 7.46 (1H, d, J = 9.4 Hz).— 774

1H-NMR (CDCl3) δ ppm: 1.09-1.16 (19H, m), 1.20 (3H, s), 1.23-1.32 (5H,m)m 1.33- 1.48 (2H, m), 1.61-1.90 (7H, m), 2.81-2.91 (2H, m), 3.49-3.55(1H, m), 3.55-3.63 (1H, m), 6.40 (1H, d, J = 3.4 Hz), 7.21 (1H, d, J =3.4 Hz), 7.31 (1H, d, J = 2.8 Hz), 8.06 (1H, d, J = 2.7 Hz). — 775

1H-NMR (CDCl3) δ ppm: 1.07-1.17 (19H, m), 1.21 (3H, s), 1.23-1.35 (5H,m), 1.37- 1.49 (2H, m), 1.83-1.90 (6H, m), 1.36-2.09 (1H, m), 3.05 (1H,d, J = 12.6 Hz), 3.36 (1H, d, J = 12.5 Hz), 3.48-3.54 (1H, m), 3.94-4.02(1H, m), 6.33 (1H, d, J = 5.6 Hz), 6.54 (1H, d, J = 3.6 Hz), 7.10 (1H,d, J = 3.6 Hz), 7.98 (1H, d, J = 5.5 Hz). — 776

1H-NMR (CDCl3) δ ppm: 1.1-1.18 (19H, m), 1.18-1.22 (4H, m), 1.34 (3H,s), 1.36- 1.44 (2H, m), 1.61-1.84 (7H, m), 1.86-1.98 (1H, m), 2.81 (1H,d, J = 11.4 Hz), 3.07 (1H, d, J = 11.4 Hz), 3.6-3.65 (1H, m), 3.65- 3.75(1H, m), 6.30 (1H, dd, J = 3.0, 8.2 Hz), 6.86 (1H, dd, J = 8.2, 12.0Hz), 8.24 (1H, d, J = 3.1 Hz). —

TABLE 85 absolute configuration

Example R⁴ NMR Salt 777

1H-NMR (CDCl3) δ ppm: 1.07 (1H, br), 1.16-1.33 (8H, m), 1.35-1.50 (2H,m), 1.64- 1.88 (4H, m), 2.81 (1H, d, J = 11.8 Hz), 3.05 (1H, d, J = 11.8Hz), 3.46-3.53 (1H, m), 3.68-3.79 (1H, m), 6.71 (1H, s), 6.92 (1H, d, J= 2.0, 9.0 Hz), 7.5-7.6 (1H, m), 7.89 (1H, d, J = 0.9 Hz), 9.7 (1H, br).— 778

1H-NMR (CDCl3) δ ppm: 0.94-1.24 (6H, m), 1.33 (3H, s), 1 37-1.47 (2H,m), 1.63- 1.60 (3H, m), 1.85-2.02 (1H, m ), 3.02 (1H, d, J = 11.8 Hz),3.09 (1H, d, J = 11.9 Hz), 3.62-3.68 (1H, m), 3 83-3 92 (1H, m), 6.43(1H, d. J = 7.6 Hz), 6.97 (1H, d, J = 8.3 Hz), 7.23 (1H, dd, J = 7.7,8.1 Hz), 8.10 (1H, d, J = 0.9 Hz), 9.96 (1H, br). — 779

1H-NMR (CDCl3) δ ppm: 0.95 (1H, br), 1.15-1.35 (8H, m), 1.35-1.52 (2H,m), 1.52- 1.90 (4H, m), 2.81 (1H, d, J = 11.9 Hz), 3.03 (1H, d, J = 11.8Hz), 3.45-3.55 (1H, m), 3.65-3.8 (1H, m), 6.66 (1H, s), 6.95 (1H, dd, J= 2.1, 9.0 Hz), 7.06 (1H, dd, J = 0.8, 2.0 Hz), 7.46 (1H, d, J = 9.0Hz), 6.23 (1H, bs). — 780

1H-NMR (CDCl3) δ ppm: 0.95-1.11 (3H, m), 1.20 (3H, s), 1.28-1.44 (5H,m), 1.59- 1.79 (3H, m), 1.79-1.93 (1H, m), 2.70 (1H, d, J = 11.3 Hz),3.08 (1H, d, J = 11.3 Hz), 3.6-3.7 (2H, m), 6.35 (1H, dd, J = 3.8, 8.3Hz), 6.61 (1H, dd, J = 3.2, 5.6 Hz), 6.78 (1H, dd, J = 8.3, 10.7 Hz),7.17 (1H, dd, J = 2.8, 2.8 Hz), 6.39 (1H, br). — 781

1H-NMR (CDCl3) δ ppm: 1.01 (1H, br), 1.10-1.26 ( 5H, m), 1.28 (3H, s),1.31-1.48 (2H, m), 1.61-1.83 (4H, m), 2.81 (1H, d, J = 11.5 Hz), 2.89(1H, d, J = 11.5 Hz), 3.5-3.8 (1H, m), 3.6-3.7 (1H, m), 6.95 (1H, d, J =2.1 Hz), 7.04 (1H, dd, J = 0.8. 2.0 Hz), 7.17 (1H, dd, J = 2.3, 9.1 Hz),7.28 (1H, d, J = 9.1 Hz), 8.68 (1H, br). — 782

1H-NMR (DMSO-d6) δ ppm: 1.00-1.37 (9H, m), 1.47-1.9 (5H, m), 2.90 (2H,s), 2.95- 4.35 (4H, m), 8.27 (1H, dd, J = 1.9, 3.3 Hz), 6.49 (1H, s),7.34 (1H, dd, J = 2.9, 2.9 Hz), 7.40 (1H, d, J = 2.5 Hz), 8.04 (1H, d, J= 2.6 Hz), 11.30 (1H, s). ½ Fumarate 783

1H-NMR (CDCl3) δ ppm: 0.81-1.37 (8H, m), 1.37-1.51 (3H, m), 1.65-1.83(3H, m), 1.99-2.13 (1H, m), 3.09 (1H, d, J = 12.6 Hz), 3.4-3.5 (1H, m),3.5-3.55 (1H, m), 4.0-4.1 (1H, m), 6.36 (1H, d, J = 5.7 Hz), 6.50 (1H,d, J = 3.6 Hz), 7.1-7.2 (1H, m), 8.0-8.1 (1H, m), 9.7-10.6 (1H, m). —784

1H-NMR (CDCl3) δ ppm: 1.02-1.17 (2H, m), 1.22 (3H, s), 1.34 (3H, s),1.36-1.45 (2H, m), 1.62-1.80 (3H, m), 1.83-1.96 (1H, m), 2.64 (1H, d, J= 11.5 Hz), 3.05 (1H, d, J = 11.5 Hz), 3.65-3.7 (1H, m), 3.7-3.8 (1H,m), 6.28 (1H, dd, J = 3.3. 8.3 Hz), 6.91 (1H, dd, J = 8.2, 10.4 Hz),8.12 (1H, d, J = 3.4 Hz), 10.38 (1H, br). —

TABLE 86 absolute configuration

Example R⁴ NMR Salt 785

1H-NMR (CDCl3) δ ppm: 1.15-1.32 (9H, m), 1.33-1.50 (2H, m), 1.84-1.88(4H, m), 2.82 (1H, d, J = 11.7 Hz), 3.03 (1H, d, J = 11.7 Hz), 3.46-3.54(1H, m), 3.71-3.79 (1H, m), 3.80 (3H, s), 6.51 (1H, d, J = 1.7 Hz), 6.36(1H, dd, J = 2.1, 9.0 Hz), 7.02 (1H, s), 7.46 (1H, d, J = 9.0 Hz). — 786

1H-NMR (DMSO-d6) δ ppm: 1.0-1.25 (2H, m), 1.25-1.4 (7H, m), 1.45-1.9(5H, m), 2.94 (2H, s), 3.36 (3H, br), 3.66 (1H, br), 3.7-3.6 (4H, m)6.29 (1H, d, J = 3.3 Hz), 6.54 (2H, s), 7.39 (1H, d, J = 3.3 Hz), 7.43(1H, d, J = 2.2 Hz), 8.10 (1H, d, J = 2.5 Hz). Fumarate 787

1H-NMR (DMSO-d6) δ ppm: 1.15-1.4 (9H, m), 1.5-1.8 (4H, m), 2.0-2.15 (1H,m), 3.09 (1H, d, J = 12.9 Hz), 3.43 (1H, d, J = 12.4 Hz), 3.55-3.65 (1H,m), 3.73 (3H, s), 4.05-4.15 (1H, m), 6.41 (1H, d, J = 5.6 Hz), 6.49 (1H,d, J = 3.8 Hz), 6.55 (2H, s), 7.26 (1H, d, J = 3.6 Hz), 7.93 (1H, d, J =5.6 Hz). Fumarate 788

1H-NMR (DMSO-d6) δ ppm: 0.97-1.13 (2H, m), 1.33-1.44 (1H, m), 1.51 (3H,s), 1.53 (3H, s), 1 58-1.67 (1H, m), 1.67-1.96 (3H, m), 1.96-2.07 (1H,m), 3.00 (1H, d, J = 12.9 Hz), 3.26 (1H, d, J = 13.0 Hz), 3.85-4.0 (1H,m), 4.05-4.2 (4H, m), 6.40 (1H, dd, J = 3.0, 8.3 Hz), 7.05 (1H, dd, J =8.2, 11.8 Hz), 8.0-8.2 (1H, m), 8.38 (1H, d, J = 2.3 Hz), 9.65-9.9 (1H,m). Hydrochloride 789

1H-NMR (DMSO-d6) δ ppm: 1.00-1.16 (2H, m), 1.34-144 (1H, m), 1.50 (3H,s), 1.53 (3H, s), 1.58-1.96 (4H, m), 1.98-2.09 (1H, m), 2.98 (1H, d, J =12.9 Hz), 3.24 (1H d, J = 13.0 Hz), 3.85-3.95 (1H, m), 3.95-4.08 (1H,m), 4.17 (3H, s), 6.24 (1H, dd, J = 3.2, 8.0 Hz), 6.85 (1H, dd, J = 8.0,11.5 Hz), 7 95-8.2 (1H, m), 8.74 (1H, d, J = 2.8 Hz), 9.7-10.0 (1H, m).Hydrochloride

TABLE 87 absolute configuration

Example R⁴ NMR Salt 790

1H-NMR (DMSO-d6) δ ppm: 1.01-1.25 (2H, m), 1.32-1.42 (1H, m), 1.46 (3H,s), 1.48 (3H, s), 1 58-2.03 (6H, m), 2.05-2.18 (1H, m), 2.70-2.93 (5H,m), 3.24 (1H, d. J = 12.9 Hz), 3.45-3.57 (1H, m), 3.81-3.93 (1H, m),6.53 (1H, d, J = 11.4 Hz), 6.70 (1H, d, J = 8.4 Hz), 8.02 (1H, br), 9.72(1H, br). Hydrochloride 791

1H-NMR (DMSO-d6) δ ppm: 0.90-1.21 (2H, m), 1.28-1.41 (1H, m), 1.48 (6H,s), 1.57- 1.67 (1H, m), 1.67-2.08 (5H, m), 2.08-2.21 (1H, m), 2.70 (1H,d, J = 12.4 Hz), 2.78-3.00 (4H, m ), 3.22-3.42 (2H, m), 3.77-3.92 (1H,m), 8.74 (1H, dd, J = 4.3, 8.6 Hz), 6.88 (1H, dd, J = 8.6, 8.0 Hz), 8.01(1H, br), 9.73 (1H, br). Hydrochloride 792

1H-NMR (CDCl3) δ ppm: 0.75-1.15 (3H, m), 1.17 (3H, s), 1.27 (3H, s),1.3-1.45 (2H, m), 1.45-1.75 (3H, m), 1.75-1.95 (1H, m), 1.95-2.1 (1H,m), 2.1-2.25 (1H, m), 2.52 (1H, d, J = 11.2 Hz), 2.85-3.05 (5H, m),3.1-3.2 (1H, m), 3.45-3.55 (1H, m), 6.53 (1H, d, J = 8.4 Hz), 7.03 (1H,d, J = 8.4 Hz). — 793

1H-NMR (DMSO-d6) δ ppm: 1.11-1.24 (1H, m ), 1.34-1.42 (1H, m), 1.45 (3H,s), 1.47 (3H, s), 1.59-2.03 (6H, m), 2.05-2.17 (1H, m), 2.7-2.95 (5H,m), 3.27 (1H, d, J = 12.9 Hz), 3.38-3.55 (1H, m), 3.79-3.95 (1H, m),4.28-4.11 (1H, m), 6.72 (1H, d, J = 1.5 Hz), 6.94 (1H, s), 7.9-8.1 (1H,m), 9.6- 9.8 (1H, m). Hydrochloride 794

1H-NMR (DMSO-d6) δ ppm: 1.20-1.46 (6H, m), 1.52 (3H, s), 1.82-1.93 (4H,m), 1.96- 2.12 (1H, m), 2.97 (1H, d, J = 13.4 Hz), 3.29 (1H, d, J = 13.4Hz ), 3.7-3.85 (1H, m), 3.9- 4.05 (1H, m), 6.70 (1H, dd, J = 2 4, 8.9Hz), 7.12 (1H, d, J = 2.4 Hz), 7.23 (1H, d, J = 8.9 Hz), 8.18 (1H, br),9.94 (1H, br). Hydrochloride 795

1H-NMR (DMSO-d6) δ ppm: 1.1-1.25 (9H, m), 1.25-1.35 (1H, m), 1.45-1.75(4H, m), 1.9-2.05 (1H, m), 2.94 (1H, d, J = 12.2 Hz), 3.07 (1H, d, J =12.3 Hz), 3.11-3.62 (3H, m). 3.83-3.71 (1H, m), 6.57 (2H, s), 6.72 (1H,d, J = 8.0 Hz), 8.75-6.81 (1H, m), 7.04 (1H, dd, J = 8.3, 8.3 Hz).Fumarate 796

1H-NMR (CDCl3) δ ppm: 0.65-1.3 (9H, m), 1.3-1.95 (6H, m), 2.89 (1H, d, J= 11.5 Hz), 2.79 (1H, d, J = 11.6 Hz), 3.4-3.56 (2H, m), 5.64-5.90 (2H,m), 6.25 (1H, dd, J = 11.6 Hz), 6.51 (1H, d, J = 2.4 Hz), (6.89 (1H, d,J = 8.5 Hz). —

TABLE 88 absolute configuration

Example R⁴ NMR Salt 797

1H-NMR (CDCl3) δ ppm: 1.01-1.13 (19H, m), 1.14-1.28 (11H, m), 1.31-1.48(2H, m), 1.60-1.70 (4H, m), 2.67 (1H, d, J = 11.6 Hz), 2.63 (1H, d, J =11.5 Hz), 3.4-3.55 (2H, m), 6.69-6.74 (2H, m), 6.74-6.60 (2H, m). — 798

1H-NMR (CDCl3) δ ppm: 1.07-1.16 (19H, m), 1.18-1.33 (11H, m), 1.33-1.47(2H, m), 1.62-1.80 (4H, m), 2.68 (1H, d, J = 12.0 Hz), 2.97 (1H, d, J =11.9 Hz), 3.4-3.45 (1H, m), 3.55-3.6 (1H, m), 6.25-6.35 (1H, m), 6.37(1H, dd, J = 2.4. 7.8 Hz), 6.43 (1H, dd, J = 1.9, 8.3 Hz), 7.03 (1H, dd,J = 8.1, 8.1 Hz). — 799

1H-NMR (CDCl3) δ ppm: 1.07-1.14 (19H, m), 1.14-1.29 (11H, m), 1.29-1.47(2H, m), 1.59-1.77 (4H, m), 2.70 (1H, d, J = 11.7 Hz), 2.92 (1H, d, J =11.7 Hz), 3.4-3.5 (1H, m), 3.55-3.65 (1H, m), 3.75 (3H, s), 4.78-4.89(2H, m), 6.65 (1H, dd, J = 3.1, 8.8 Hz), 6.71 (1H, d, J = 8.8 Hz). 7.22(1H, d, J = 3.0 Hz). — 800

1H-NMR (CDCl3) δ ppm: 1.06-1.13 (18H, m), 1.14-1.29 (12H, m), 1.32-1.48(2H, m), 1.48-1.76 (4H, m), 2.65 (1H, d, J = 11.8 Hz), 2.83 (1H, d, J =11.8 Hz), 3.35-3.45 (1H, m), 3.45-3.55 (1H, m), 6.39-6.48 (1H, m), 6.55(1H, dd, J = 2.9, 14.1 Hz), 6.79 (1H, dd, J = 9.4, 9.4 Hz). — 801

1H-NMR (CDCl3) δ ppm: 1.11 (18H, d, J = 7.2 Hz), 1.15-1.21 (4H, m),1.21-1.33 (7H, m), 1.34-1.47 (2H, m), 1.47-1.77 (5H, m), 2.66 (1H, d, J= 11.5 Hz), 2.61 (1H, d, J = 11.6 Hz), 3.4-3.55 (2H, m), 6.61 (1H, d, J= 3.0. 8.9 Hz), 6.78 (1H, d, J = 8.9 Hz), 6.81 (1H, d, J = 3.0 Hz). —802

1H-NMR (CDCl3) δ ppm: 1.04-1.11 (18H, m), 1.11-1.22 (7H, m)m 1.23 (3H,s), 1.26- 1.49 (4H, m), 1.64-1.79 (4H, m), 2.71 (1H, d, J = 11.8 Hz),3.01 (1H, d, J = 11.9 Hz), 3.4-3.5 (1H, m), 3.6-3.7 (1H, m), 4.73 (2H,s), 6.79-6.86 (2H, m), 7.18-7.23 (2H, m), — 803

1H-NMR (CDCl3) δ ppm: 1.03-1.12 (18H, m), 1.12-1.48 (13H, m), 1.50-1.82(5H, m), 2.70 (1H, d, J = 12.0 Hz), 2.99 (1H, d, J = 12.0 Hz), 3.35-3.45(1H, m), 3.55-3.65 (1H, m), 4.77 (2H, s), 6.47 (1H, dd, J = 2.4, 14.0Hz), 6.61 (1H, dd, J = 2.4, 8.6 Hz), 7.32 (1H, dd, J = 8.8, 8.8 Hz). —804

1H-NMR (CDCl3) δ ppm: 1.03 (18H, d, J = 2.4 Hz), 1.13-1.27 (9H, m),1.27-1.77 (6H, m), 2.67 (1H, d, J = 11.6 Hz), 2.80 (1H, d, J = 11.5 Hz),3.4-3.55 (2H, m), 4.96 (2H, s), 6.42 (1H, d, J = 2.9 Hz), 6.70 (1H, dd,J = 2.0, 8.8 Hz), 6.80 (1H, d, J = 8.8 Hz). —

TABLE 89 absolute configuration

Example R⁴ NMR Salt 805

1H-NMR (CDCl3) δ ppm: 1.00-1.48 (11H, m ), 1.54-1.871 (4H, m), 2.70 (1H,d, J = 10.4 Hz), 2.81 (1H, d, J = 11.5 Hz), 3.3-3.65 (2H, m), 6.75 (4H,bs). — 806

1H-NMR (CDCl3) δ ppm: 1.14-1.49 (11H, m), 1.60-1.83 (4H, m), 2.71 (1H,d, J = 12.1 Hz), 3.03 (1H, d, J = 12.0 Hz), 3.37-3.44 (1H, m), 3.56-3.67(1H, m), 6.16-6.23 (1H, m), 6.33 (1H, dd, J = 2.3, 2.3 Hz), 6.43 (1H,dd, J = 2.1, 8.4 Hz), 7.06 (1H, dd, J = 8.1, 8.1 Hz). — 807

1H-NMR (DMSO-d6) δ ppm: 1.0-1.25 (2H, m), 1.25-1.4 (7H, m), 1-4-1.85(5H, m), 2.78 (1H, d, J = 12.3 Hz), 2.90 (1H, d, J = 12.1 Hz), 2.95-4.1(9H, m), 4.44 (2H, s), 6.50 (2H, s), 6.71 (1H, dd, J = 2.8, 8.6 Hz),6.79 (1H, d, J = 6.9 Hz), 6.97 (1H, d, J = 2.7 Hz). Fumarate 808

1H-NMR (CDCl3) δ ppm: 1.10-1.27 (9H, m), 1.31-1.48 (1H, m), 1.49-2.01(6H, m), 2.68 (1H, d, J = 11.5 Hz), 2.76 (1H, d, J = 11.5 Hz), 3.4-3.55(2H, m), 6.73 (1H, dd, J = 2.8, 8.9 Hz), 6.78 (1H, d, J = 2.8 Hz), 6.89(1H, d, J = 8.9 Hz). — 809

1H-NMR (CDCl3) δ ppm: 1.17-1.61 (12H, m), 1.62-1.83 (4H, m), 2.72 (1H,d, J = 11.9 Hz), 3.03 (1H, d, J = 11.9 Hz), 3.4-3.45 (1H, m), 3.6-3.7(1H, m), 4.56 (2H, s), 6.80-6.86 (2H, m), 7.20-7.25 (2H, m). — 810

1H-NMR (CDCl3) δ ppm: 0.91 (1H, br), 1.17-1.43 (10H, m), 1.56 (1H, br),1.62-1.84 (4H, m), 2.71 (1H, d, J = 12.1 Hz), 3.02 (1H, d, J = 12.0H),3.35-3.45 (1H, m), 3.55- 3.65 (1H, m), 4.82 (2H, d, J = 3.2 Hz), 6.51(1H, dd, J = 2.5, 14.0 Hz), 6.59 (1H, dd, J = 2.5, 8.5 Hz), 7.19 (1H,dd, J = 8.8, 8.8 Hz). — 811

1H-NMR (CDCl3) δ ppm: 0.92-1.02 (1H, m), 1.02-1.13 (4H, m), 1.15 (3H,s), 1.21- 1.30 (1H, m), 1.35-1.65 (5H, m), 1.69-1.83 (1H, m), 2.60 (1H,d, J = 11.3 Hz), 2.69 (1H, d, J = 11.3 Hz), 3.32 (1H, br), 3.41-3.49(1H, m), 4.43 (2H, d, J = 4.8 Hz), 4.88 (1H, t, J = 5.4 Hz), 6.55 (1H,dd, J = 2.8, 8.7 Hz), 6.60 (1H, d, J = 8.6 Hz), 6.83 (1H, d, J = 2.7Hz), 8.55 (1H, s). —

TABLE 90 absolute configuration

Example R⁵ R⁶ R⁷ R⁸ R⁹ NMR Salt 812 —H —H —OCH3 —H —H 1H-NMR (DMSO-d6) δppm: 1.1-1.3 (2H, m), 1.35-1.45 (4H, m), 1.52 (3H, s), 1.6-1.9 (4H, m),1.95-2.1 (1H, m), 2.93 (1H, d, J = 13.1 Hz), 3.11 (1H, d, J = 13.0 Hz),3.68 (3H, s), 3.7-3.9 (2H, m), 4.35-5.35 (1H, m), 6.75-6.35 (2H, m),6.85-6.95 (2H, m), 8.09 (1H, br), 9.90 (1H, br). 2 Hydrochloride 813—CH3 —Cl —H —H —H 1H-NMR (CDCl3) δ ppm: 0.93-1.09 (3H, m), 1.16 (3H, s),1.23- 1.34 (4H, m), 1.34-1.44 (2H, m), 1.44-1.75 (2H, m), 1.79-1.92 (1H,m), 2.37 (3H, s), 2.41 (1H, d, J = 11.0 Hz), 2.83-2.91 (1H, m), 3.10(1H, d, J = 11.1 Hz), 3.51-3.57 (1H, m), 6.79 (1H, dd, J = 2.1, 7.1 Hz),6.99-7.08 (2H, m). — 814 —CH3 —H —H —H —H 1H-NMR (CDCl3) δ ppm:0.78-1.13 (3H, m), 1.16 (3H, s), 1.28- 1.42 (5H, m), 1.54-1.76 (4H, m),1.81-1.95 (1H, m), 2.34 (3H, s), 2.43 (1H, d, J = 11.1 Hz), 2.87-2.96(1H, m), 3.13 (1H, d, J = 11.1 Hz), 3.47-3.58 (1H, m), 6.88 (1H, dd, J =1.0, 7.9 Hz), 6 91-6.97 (1H, m), 7.07- 7.15 (1H, m), 7.17 (1H, (dd, J =0.7, 7.5 Hz). Hydrochloride 815 —H —H —CH3 —H —H 1H-NMR (DMSO-d6) δ ppm:1.16-1.33 (2H, m), 1.34-1.48 (4H, m), 1.49-1.56 (3H, m), 1.61- 1.93 (4H,m), 1.97-2.11 (1H, m), 2.19 (3H, s), 2.91 (1H, d, J = 13.2 Hz),3.19-3.32 (1H, m), 3.68- 3.80 (1H, m), 3.87-3.99 (1H, m), 4.35-8.4 (1H,m), 6.83 (2H, d, J = 8.4 Hz), 7.02 (2H, d, J = 3.1 Hz), 8.0-8.35 (1H,m), 9.8-10.2 (1H, m). 2 Hydrochloride 816 —CH3 —CH3 —H —H —H 1H-NMR(DMSO-d6) δ ppm: 0.96-1.18 (2H, m), 1.26-1.45 (1H, m), 1.49 (3H, s),1.52 (3H, s), 1.56-1.67 (1H, m), 1.67-1.63 (2H, m), 1.83- 2.10 (2H, m).2.20 (3H, s), 2.22 (3H, s), 2.59 (1H, d, J = 12.6 Hz), 3.0- 3.15 (1H,m), 3.25-3.4 (1H, m), 3.8-3.05 (1H, m), 6.82 (1H, d, J = 7.8 Hz), 6.90(1H, d, J = 7.4 Hz), 7.03 (1H, dd, J = 7.7, 7.7 Hz), 8.02 (1H, br),9.65-9.9 (1H, m). Hydrochloride 817 —H —CH3 —Cl —H —H 1H-NMR (DMSO-d6) δppm: 1.21-1.49 (6H, m), 1.53 (3H, s), 1.63- 1.96 (4H, m), 1.96-2.16 (1H,m), 2.28 (3H, s), 2.93 (1H, d, J = 13.5 Hz), 3.36 (1H, d, J = 13.4 Hz),3.65-3.8 (1H, m), 3.95- 4.05 (1H, m), 4.43 (1H, br), 6.79 (1H, dd, J =2.9, 8.8 Hz), 6.93 (1H, d, J = 2.8 Hz), 7.20 (1H, d, J = 8.8 Hz),8.1-8.4 (1H, m), 9.8-10.2 (1H, m). Hydrochloride 818 —H —CH3 —F —H —H1H-NMR (DMSO-d6) δ ppm: 1.16-1.35 (2H, m), 1.35-1.48 (4H, m), 1.62 (3H,s), 1.82-1-95 (4H, m), 1.95-2.14 (1H, m), 2.18 (3H, d, J = 1.6 Hz), 2.93(1H, d, J = 13.2 Hz), 3.21 (1H, d, J = 13.1 Hz), 3.7-3.8 (1H, m),3.85-4.0 (1H, m), 4.05- 5.8 (1H, m), 8.71- 6.81 (1H, m), 6.86 (1H, dd, J= 2.9, 6.8 Hz), 6.97 (1H, dd, J = 9.1, 9.1 Hz), 8.05- 6.3 (1H, m), 9.85-10.2 (1H, m). Hydrochloride 819 —CH3 —F —H —H —H 1H-NMR (DMSO-d6) δ ppm:0.98-1.20 (2H, m), 1.3-1.43 (1H, m), 1.50 (3H, s), 1.51 (3H, s),1.56-1.69 (1H, m), 1.69-1.87 (2H, m), 1.87- 2.08 (2H, m), 2.20 (3H, d, J= 2.3 Hz), 2.67 (1H, d, J = 12.6 Hz), 3.15-3.25 (1H, m), 3.36 (1H, d, J= 12.8 Hz), 3.8-4.0 (1H, m), 6.83 (1H, d, J = 8.0 Hz), 6.89 (1H, dd, J =8.8 (8.8 Hz), 7.16 (1H, dd, J = 7.9, 15.2 Hz), 8.08 (1H, br), 9.7-10.0(1H, m). Hydrochloride 820 —H —F —CH3 —H —H 1H-NMR (DMSO-d6) δ ppm:1.14-1.41 (9H, m), 1.50-1.90 (5H, m), 2.09 (3H, d, J = 0.8 Hz), 2.78(1H, d, J = 12.8 Hz), 3.19 (1H, d, J = 12.3 Hz), 3.5-3.6 (1H, m),3.8-3.9 (1H, m), 6.52 (2H, s), 6.60-6.71 (2H, m), 7.05 (1H, dd, J = 8.9,8.9 Hz). Fumarate 821 —H —Cl —CH3 —H —H 1H-NMR (DMSO-d6) δ ppm:1.15-1.40 (9H, m), 1.5-1.9 (5H, m), 2.19 (3H, d, J = 0.6 Hz), 2.78 (1H,d, J = 12.7 Hz), 3.18 (1H, d, J = 12.7 Hz), 3.5-3.8 (1H, m), 3.8-3.9(1H, m), 6.54 (2H, s), 6.80 (1H, dd, J = 2.6, 8.5 Hz), 8.90 (1H, d, J =2.6 Hz), 7.13 (1H, d, J = 8.5 Hz). Fumarate 822 —H —Cl —H —H —H 1H-NMR(DMSO-d6) δ ppm: 1.12-1.21 (4H, m), 1.22 (3H, s), 1.24- 1.37 (2H, m),1.45-1.77 (4H, m), 1.77-1.92 (1H, m), 2.72 (1H, d, J = 12.5 Hz), 3.18(1H, d, J = 12.4 Hz), 3.40 (1H, brs), 3.75-3.85 (1H, m), 6.50 (1H, s),8.67 (1H, dd, J = 1.6, 7.7 Hz), 6.8-6.9 (2H, m), 7.16 (1H, dd, J = 8.1,6.1 Hz). ½ Fumarate 823 —CH3 —OCH3 —H —H —H 1H-NMR (DMSO-d6) δ ppm:1.0-1.17 (2H, m), 1.29-1.43 (1H, m), 1.48 (3Hm s), 1.51 (3H, s),1.56-2.05 (5H, m), 2.12 (3H, s), 2.62 (1H, d, J = 12.6 Hz), 3.05-3.2(1H, m), 3.3-3.4 (1H, m), 3.76 (3H, s), 3.85-3.95 (1H, m), 8.61 (1H, d,J = 7.9 Hz), 8.72 (1H, d, J = 8.2 Hz), 7.10 (1H, dd, J = 8.1, 8.1 Hz),7.99 (1H, br), 9.5-9.8 (1H, m). Hydrochloride 824 —H —H —OCHF2 —H —H1H-NMR (DMSO-d6) δ ppm: 1.21-1.36 (2H, m), 1.36-1.48 (4H, m), 1.52 (3H,s), 1.63-1.02 (4H, m), 1.93-2.09 (1H, m), 2.94 (1H, d, J = 13.4 Hz),3.33 (1H, d, J = 13.3 Hz), 3.5-4.4 (2H, m), 6.84-7.26 (5H, m), 8.13 (1H,br), 9.84 (1H, br). 2 Hydrochloride 825 —H —H —OCF3 —H —H 1H-NMR(DMSO-d6) δ ppm: 1.26-1.48 (6H, m), 1.50 (3H, s), 1,63- 1.32 (4H, m),1.92-2.06 (1H, m), 2.96 (1H, d, J = 13.6 Hz), 3.44 (1H, d, J = 13.5 Hz),3.72-3.83 (1H, m), 3.96-4.09 (1H, m), 6.96-7.07 (2H, m), 7.15- 7.27 (2H,m), 8.08 (1H, br), 9.67 (1H, br). Hydrochloride 826 —H  Cl —CN —H —H1H-NMR (DMSO-d6) δ ppm: 1.10 (3H, s), 1.15-1.25 (4H, m), 1.25- 1.45 (2H,m), 1.45-1.75 (4H, m), 1.85-2.0 (1H, m), 2.75 (1H, d, J = 13.0 Hz),2.9-3.85 (4H, m), 3.85-3.95 (1H, m), 6.56 (1H, s), (1H, dd, J = 2.5, 9.1Hz), 7.09 (1H, d, J = 2.4 Hz), 7.59 (1H, d, J = 9.0 Hz). ½ Fumarate 827—H —F —OCF3 —H —H 1H-NMR (DMSO-d6) δ ppm: 1.28-1.46 (6H, m ), 1.51 (3H,s), 1.63- 2.10 (5H, m), 2.97 (1H, d, J = 13.8 Hz), 3.54 (1H, d, J = 13.8Hz), 3.65-3.8 (1H, m), 4.0-4.15 (1H, m), 6.81 (1H, dd, J = 2.2, 9.2 Hz),7.05 (1H, dd, J = 2.8, 14.4 Hz), 7.34 (1H, dd, J = 9.2, 9.2 Hz), 8.22(1H, br), 9.89 (1H, br). Hydrochloride 828 —H —F —OCHF2 —H —H 1H-NMR(DMSO-d6) δ ppm: 1.09-1.37 (9H, m), 1.44-1.73 (4H, m), 1.75-1.90 (1H,m), 2.66 (1H, d, J = 12.1 Hz), 3.0- 3.7 (4H, m), 3.7-3.8 (1H, m), 6.52(1H, m), 6.67 (1H, d, J = 2.1, 9.3 Hz), 6.30-7.22 (3H, m) ½ Fumarate 829—H  Cl —OCHF2 —H —H 1H-NMR (DMSO-d6) δ ppm: 1.08-1.37 (9H, m), 1.43-1.59(1H, m), 1.59-1.74 (3H, m), 1.75- 1.30 (1H, m), 2.59 (1H, d, J = 12.3Hz), 2.8-4.2 (5H, m), 6.52 (1H, s). 6.82-7.25 (4H, m). ½ Fumarate 830 —H—OCHF2 —H —H —H 1H-NMR (DMSO-d6) δ ppm: 1.13-1.41 (9H, m), 1.46-1.93(5H, m), 2.75 (1H, d, J = 12.5 Hz), 2.8-4.4 (6H, m), 6.46 (1H, d, J =3.1 Hz), 6.54 (2H, s), 6.82 (1H, s), 6.76 (1H, dd, J = 8.4 Hz), 7.0-7.4(2H, m). ½ Fumarate 831 —H —OCHF2 —F —H —H 1H-NMR (DMSO-d6) δ ppm:1.02-1.36 (9H, m), 1.44-1.59 (1H, m), 1.59-1.74 (3H, m), 1.74- 1.67 (1H,m), 2.65-4.5 (6H, m), 6.52 (1H, s), 6.7-6.8 (2H, m), 7.0-7.4 (2H, m). ½Fumarate 832 —H —OCHF2 —Cl —H —H 1H-NMR (DMSO-d6) δ ppm: 1.10-1.38 (9H,m), 1.44-1.74 (4H, m), 1.76-1.91 (1H, m), 2.69 (1H, d, J = 12.3 Hz),2.75-4.2 (5H, m), 6.53 (1H, s), 6.75-6.85 (2H, m), 7.05-7.45 (2H, m). ½Fumarate 833 —H —CN —OCHF2 —H —H 1H-NMR (DMSO-d6) δ ppm: 1.06-1.23 (7H,m), 1.23-1.37 (2H, m), 1.43-1.74 (4H, m), 1.75- 1.88 (1H, m ), 2.69 (1H,d, J = 12.4 Hz), 2.9-3.75 (4H, m), 3.75-3.85 (1H, m}, 6.53 (1H, s),7.00- 7.41 (4H, m). ½ Fumarate 834 —H —OCHF2 —OCHF2 —H —H 1H-NMR(DMSO-d6) δ ppm: 1.1-1.4 (9H, m), 1.44-1.78 (4H, m), 1.76- 1.90 (1H, m),2.69 (1H, d, J = 12.2 Hz), 2.8-4.25 (5H, m), 6.52 (1H, s), 6.71-7.36(5H, m). ½ Fumarate 835 —H —F —OCHF2 —F —H 1H-NMR (DMSO-d6) δ ppm:1.08-1.23 (7H, m), 1.24-1.40 (2H, m), 1.43-1.73 (4H, m), 1.76- 1.91 (1H,m), 2.67 (1H, d, J = 12.5 Hz), 2.0-4.2 (5H, m), 6.53 (1H, s), 6.67-6.77(2H, m), 7.05 (1H, t, J = 72.9 Hz). ½ Fumarate 836 —H —H —OCH2CHF2 —H —H1H-NMR (DMSO-d6) δ ppm: 1.13-1.31 (2H, m), 1.32-1.47 (4H, m), 1.53 (3H,s), 1.61-1.90 (4H, m), 1.37-2.12 (1H, m), 2.83 (1H, d, J = 13.1 Hz),3.15 (1H, d, J = 13.1 Hz), 3.69-3.81 (1H, m), 3.33-3.33 (1H, m),4.10-4.46 (3H, m), 6.12- 6.53 (1H, m), 6.90 (4H, s), 8.0-8.25 (1H, m),9.9-10.1 (1H, m). 2 Hydrochloride 837 —H —F —OCH2CHF2 —H —H 1H-NMR(DMSO-d6) δ ppm: 1.20-1.46 (6H, m), 1.51 (3H, s), 1.63- 1.91 (4H, m),1.93-2.10 (1H, m), 2.91 (1H, d, J = 13.4 Hz), 3.29 (1H, d, J = 13.2 Hz),3.67-3.80 (1H, m), 3.89-4.01 (1H, m), 4.20-4.35 (2H, m), 6.16- 6.51 (1H,m), 6.68 (1H, dd, J = 1.8, 9.1 Hz), 6.91 (1H, dd, J = 2.9, 14.7 Hz),7.10 (1H, dd, J = 9.5, 9.5Hz), 8.05-8.2 (1H, m), 9.75-9.95 (1H, m).Hydrochloride 838 —H —CH3 —OCHF2 —H —H 1H-NMR (DMSO-d6) δ ppm: 1.06-1.15(1H, m), 1.15-1.38 (8H, m), 1.42-1.88 (5H, m), 2.17 (3H, s), 2.68 (1H,d, J = 12.1 Hz), 3.04 (1H, d, J = 12.1 Hz), 3.1-3.8 (4H, m), 6.50 (1H,s), 6.71 (1H, dd, J = 2.9, 8.9 Hz), 6.75-7.16 (3H, m). ½ Fumarate 839 —H—OCH3 —OCHF2 —H —H 1H-NMR (DMSO-d6) δ ppm: 1.10-1.39 (9H, m), 1.45-1.90(5H, m), 2.72 (1H, d, J = 12.2 Hz), 2.95-4.1 (8H, m), 6.40 (1H, dd, J =2.8, 8.9 Hz), 6.50 (1H, s), 6.57 (1H, d, J = 2.7 Hz), 6.63-7.03 (2H, m).½ Fumarate 840 —OCHF2 —H —H —H —H 1H-NMR (DMSO-d6) δ ppm: 0.94-1.14 (1H,m ), 1.14-1.17 (1H, m), 1.18 (3H, s), 1.26 (3H, s), 1.29-1.55 (3H, m),1.59-1.73 (3H, m), 1.76- 1.90 (1H, m), 2.49 (1H, d, J = 11.2 Hz), 3.04(1H, d, J = 11.2 Hz), 3.5-3.6 (2H, m), 6.55 (1H, dd, J = 70.2, 81.4 Hz),6.91 (1H, dd, J = 1.4, 8.0 Hz), 6.93-6.99 (1H, m), 7.07- 7.18 (2H, m) —

TABLE 91 absolute configuration

Example R⁴ NMR Salt 841

1H-NMR (DMSO-d6) δ ppm: 0.95-1.15 (2H, m), 1.35-1.45 (1H, m), 1.51 (3H,s), 1.56 (3H, s), 1.6-2.05 (5H, m), 2.87 (1H, d, J = 12.8 Hz), 3.3-3.4(1H, m), 3.65-3.75 (1H, m), 4.1-4.2 (1H, m), 7.05 (1H, s), 7.35-7.45(2H, m), 7.9-8.1 (3H, m), 9.5-9.7 (1H, m). Hydrochloride 842

1H-NMR (CDCl3) δ ppm: 0.89-1.18 (5H, m), 1.25-1.74 (9H, m), 1.74-1.86(1H, m), 2.19 (3H, d, J = 0.9 Hz), 2.62 (1H, d, J = 11.2 Hz), 2.93 (1H,d, J = 11.2 Hz), 3.03-3.10 (1H, m), 3.47-3.52 (1H, m), 6.35 (1H, d, J =3.3 Hz), 6.84-6.88 (1H, m). —

TABLE 92 relative configuration

Example R⁴ NMR Salt 843

1H-NMR (CDCl3) δ ppm 1.13-1.24 (1H, m), 1.25-1.36 (2H, m), 1.60-1.83(3H, m), 1.64 (3H, s), 1.74 (3H, s), 1.89-2.02 (1H, m), 2.32- 2.37 (1H,m), 2.80 (1H, d, J = 12.5 Hz), 3.12- 3.16 (1H, m), 3.22-3.29 (1H, m),3.36 (1H, d, J = 12.5 Hz), 7.19-7.22 (2H, m), 7.29-7.33 (2H, m), 9.52(1H, brs), 9.81 (1H, brs) Hydrochloride 844

1H-NMR (DMSO-d6) δ ppm: 1.00-1.98 (13H, m), 1.98-2.28 (1H, br),2.65-3.90 (4H, br), 4.18 (3H, s), 6.70-7.95 (3H, m), 8.22-8.60 (1H, br),8.80-11.33 (3H, brm). 2 Hydrochloride

TABLE 93 absolute configuration

Example R⁴ NMR Salt 845

1H-NMR (CDCl3) δ ppm: 1.03-1.17 (23H, m), 1.17-1.41 (6H, m), 1.43 (3H,s), 1.59-1.68 (1H, m), 1.68-1.80 (3H, m), 2.32-2.40 (1H, m), 2.68 (1H,d, J = 11.3 Hz), 2.78-2.85 (1H, m), 2.88 (1H, d, J = 11.3 Hz), 7.08 (1H,dd, J = 2.4, 8.8 Hz), 7.16 (1H, d, J = 2.4 Hz), 7.22 (1H, dd, J = 2.1,8.7 Hz), 7.37 (1H, d, J = 1.8 Hz), 7.57-7.64 (2H, m). — 846

1H-NMR (CDCl3) δ ppm: 0.82-1.17 (23H, m), 1.20-1.46 (9H, m), 1.60-1.70(1H, m), 1.70- 1.85 (3H, m), 2.35-2.45 (1H, m), 2.69 (1H, d, J = 11.3Hz), 2.77-2.88 (1H, m), 2.91 (1H, d, J = 11.3 Hz), 7.02 (1H, dd, J =2.4, 8.8 Hz), 7.09- 7.15 (2H, m), 7.27 (1H, d, J = 1.9 Hz), 7.60- 7.68(2H, m). — 847

1H-NMR (CDCl3) δ ppm: 0.97-1.14 (29H, m), 1.43 (3H, s), 1.60-1.70 (1H,m), 1.70-1.80 (3H, m), 2.35-2.43 (1H, m), 2.69 (1H, d, J = 11.3 Hz),2.78-2.87 (1H, m), 2.89 (1H, d, J = 11.3 Hz), 7.11 (1H, d, J = 8.9 Hz),7.34 (1H, dd, J = 2.1, 9.0 Hz), 7.37 (1H, d, J = 1.9 Hz), 7.53 (1H, d, J= 8.9 Hz), 8.10 (1H, d, J = 8.9 Hz). — 848

1H-NMR (CDCl3) δ ppm: 0.74-1.42 (29H, m), 1.44 (3H, s), 1.58-1.83 (4H,m), 2.35-2.43 (1H, m), 2.68 (1H, d, J = 11.3 Hz), 2.78-2.87 (1H, m),2.91 (1H, d, J = 11.3 Hz), 3.91 (3H, s), 5.19-5.27 (2H, m), 7.21 (1H, d,J = 9.1 Hz), 7.29 (1H, d, J = 2.2, 9.1 Hz), 7.37 (1H, d, J = 2.1 Hz),7.69 (1H, d, J = 9.0 Hz), 8.16 (1H, d, J = 9.1 Hz). — 849

1H-NMR (CDCl3) δ ppm: 0.96-1.19 (23H, m), 1.19-1.42 (6H, m), 1.44 (3H,s), 1.57-1.78 (4H, m), 2.32-2.41 (1H, m), 2.71 (1H, d, J = 11.3 Hz),2.77-2.86 (1H, m), 2.87 (1H, d, J = 11.3 Hz), 3.89 (1H, s), 4.94 (2H, d,J = 1.1 Hz), 7.02 (1H, s), 7.22 (1H, dd, J = 2.0, 8.6 Hz), 7.44 (1H, d,J = 1.8 Hz), 7.64 (1H, d, J = 8.6 Hz), 7.88 (1H, s). —

TABLE 94 absolute configuration

Example R⁴ NMR Salt 850

1H-NMR (DMSO-d6) δ ppm: 0.88-1.03 (4H, m), 1.11-1.37 (6H, m), 1.45-1.68(5H, m), 2.26-2.35 (1H, m), 2.58 (1H, d, J = 10.9 Hz), 2.62-2.70 (1H,m), 2.73 (1H, d, J = 10.9 Hz), 7.02 (1H, dd, J = 2.4, 8.7 Hz), 7.05 (1H,d, J = 2.4 Hz), 7.16 (1H, dd, J = 2.1, 8.7 Hz), 7.37 (1H, d, J = 1.8Hz), 7.58 (1H, d, J = 8.8 Hz), 7.67 (1H, d, J = 8.9 Hz), 9.57 (1H, brs).— 851

1H-NMR (DMSO-d6) δ ppm: 0.88-1.02 (4H, m), 1.10-1.37 (6H, m), 1.44-1.74(5H, m), 2.32-2.41 (1H, m), 2.60 (1H, d, J = 11.1 Hz), 2.63-2.72 (1H,m), 2.80 (1H, d, J = 11.1 Hz), 6.94 (1H, dd, J = 2.4, 8.8 Hz), 7.00 (1H,dd, J = 2.0, 8.8 Hz), 7.02 (1H, d, J = 2.4 Hz), 7.21 (1H, d, J = 1.8Hz), 7.64 (2H, d, J = 8.7 Hz), 9.63 (1H, s). — 852

1H-NMR (DMSO-d6) δ ppm: 0.90-1.08 (4H, m), 1.15-1.40 (6H, m), 1.51-1.73(4H, m), 2.35-2.47 (1H, m), 2.65 (1H, d, J = 11.2 H), 2.70-2.85 (2H, m),2.90-3.75 (1H, br), 7.23 (1H, d, J = 8.9 Hz), 7.34 (1H, dd, J = 2.1, 9.0Hz), 7.46 (1H, d, J = 2.0 Hz), 7.70 (1H, d, J = 8.9 Hz), 7.92 (1H, d, J= 9.0 Hz), 9.05-11.25 (1H, br). — 853

1H-NMR (DMSO-d6) δ ppm: 0.95-1.10 (4H, m), 1.17-1.40 (6H, m), 1.56-1.80(4H, m), 2.49-2.60 (1H, m), 2.73-2.87 (2H, m), 2.92 (1H, d, J = 11.5Hz), 3.18-3.46 (1H, br), 7.10- 7.18 (2H, m), 7.50 (1H, d, J = 2.0 Hz),7.67 (1H, d, J = 8.8 Hz), 7.75 (1H, d, J = 8.7 Hz), 9.95-10.75 (1H, br).— 854

1H-NMR (DMSO-d6) δ ppm: 0.90-1.07 (4H, m), 1.13-1.37 (6H, m), 1.47-1.70(5H, m), 2.30-2.40 (1H, m), 2.61 (1H, d, J = 11.0 Hz), 2.65-2.74 (1H,m), 2.77 (1H, d, J = 11.0 Hz), 3.88 (3H, s), 4.82 (1H, t, J = 5.1 Hz),4.89 (2H, d, J = 5.1 Hz), 7.27 (1H, dd, J = 2.1, 9.1 Hz), 7.35 (1H, d, J= 9.1 Hz), 7.42 (1H, d, J = 2.1 Hz), 7.80 (1H, d, J = 9.1 Hz), 8.03 (1H,d, J = 9.1 Hz). — 855

1H-NMR (DMSO-d6) δ ppm: 0.95-1.10 (1H, m), 1.10-1.50 (9H, m), 1.53-1.73(3H, m), 1.77-1.87 (1H, m), 2.58-2.70 (1H, m), 2.85 (2H, s), 2.89-3.00(1H, m), 3.87 (3H, s), 4.61 (2H, s), 6.46 (1H, s), 7.20 (1H, dd, J =2.0, 8.7 Hz), 7.22 (1H, s), 7.46 (1H, d, J = 1.6 Hz), 7.73 (1H, d, J =8.7 Hz), 7.79 (1H, s), (3H not found) ½ Fumarate

TABLE 95 absolute configuration

Example R⁴ NMR Salt 856

1H-NMR (CDCl3) δ ppm: 0.91-1.05 (1H, m), 1.08 (3H, s), 1.12-1.62 (9H,m), 1.68-1.78 (2H, m), 2.42-2.50 (1H, m), 2.62 (1H, d, J = 11.3 Hz),2.75 (1H, d, J = 11.3 Hz), 2.91-3.00 (1H, m), 3.98 (3H, s), 6.78 (1H, d,J = 8.1 Hz), 7.20 (1H, d, J = 8.1 Hz), 7.43-7.54 (2H, m), 8.21-8.26 (1H,m), 8.50-8.54 (1H, m). — 857

1H-NMR (DMSO-d6) δ ppm: 0.93-1.22 (2H, m), 1.26-1.44 (5H, m), 1.44-1.54(1H, m), 1.56-1.77 (5H, m), 1.99-2.08 (1H, m), 2.62 (3H, s), 2.76 (1H,d, J = 12.4 Hz), 2.98-3.08 (2H, m), 3.33-3.50 (1H, m), 7.28 (1H, d, J =7.5 Hz), 7.38 (1H, d, J = 7.5 Hz), 7.54-7.61 (2H, m), 7.97-8.03 (1H, m),8.43-8.52 (1H, m), 9.10-9.25 (1H, br), 9.62-9.77 (1H, br). Hydrochloride858

1H-NMR (DMSO-d6) δ ppm: 1.00-1.30 (2H, m), 1.30-1.45 (4H, m), 1.45-1.62(2H, m), 1.62-1.81 (5H, m), 2.00-2.13 (1H, m), 2.91 (1H, d, J = 12.6Hz), 3.05-3.20 (2H, m), 3.41- 3.57 (1H, m), 3.75-4.30 (1H, br),7.61-7.77 (5H, m), 7.98-8.05 (1H, m), 8.54-8.61 (1H, m), 8.77-8.88 (2H,m), 9.19-9.35 (1H, m), 9.669.81 (1H, m). 2 Hydrochloride 859

1H-NMR (DMSO-d6) δ ppm: 0.90-1.45 (6H, m), 1.53-1.80 (7H, m), 1.97-2.12(1H, m), 2.83-3.40 (4H, m), 3.86 (3H, s), 7.05-7.25 (2H, m), 7.32 (1H,d, J = 2.4 Hz), 7.42-7.68 (1H, br), 7.75-7.87 (2H, m), 8.25-9.55 (2H,br), 9.55-10.02 (1H, br). 2 Hydrochloride 860

1H-NMR (DMSO-d6) δ ppm: 0.85-1.00 (1H, m), 1.10-1.70 (12H, m), 1.75-1.86(1H, m), 2.65-2.80 (3H, m), 2.99-3.10 (1H, m), 3.25- 3.43 (4H, m), 6.46(1H, s), 7.20-7.34 (3H, m), 7.45 (1H, dd, J = 7.0, 8.2 Hz), 7.88 (1H, d,J = 8.2 Hz), 8.07-9.40 (1H, br). ½ Fumarate 861

1H-NMR (DMSO-d6) δ ppm: 1.04-1.43 (6H, m), 1.54-1.80 (7H, m), 1.97-2.10(1H, m), 2.86-3.07 (2H, m), 3.07-3.30 (2H, m), 3.98 (3H, s), 7.43 (1H,d, J = 9.1 Hz), 7.55 (1H, d, J = 9.2 Hz), 7.66 (1H, brs), 7.95 (1H, d, J= 9.1 Hz), 8.04 (1H, d, J = 9.1 Hz), 8.11-8.95 (1H, br), 9.08-9.35 (1H,m), 9.60-9.86 (1H, m). 2 Hydrochloride 862

1H-NMR (CDCl3) δ ppm: 0.84-0.97 (1H, br), 1.03-1.17 (4H, m), 1.22-1.46(6H, m), 1.61- 1.74 (1H, m), 1.74-1.88 (3H, m), 2.45-2.55 (1H, m), 2.76(1H, d, J = 11.5 Hz), 2.82-2.90 (1H, m), 2.98 (1H, d, J = 11.5 Hz),7.38-7.43 (2H, m), 7.50 (1H, dd, J = 1.6, 8.4 Hz), 7.77- 7.88 (2H, m),8.12 (1H, s). — 863

1H-NMR (DMSO-d6) δ ppm: 1.05-1.43 (6H, m), 1.54-1.80 (7H, m), 1.98-2.10(1H, m), 2.90-3.32 (4H, m), 3.95 (3H, s), 6.91 (1H, d, J = 7.2 Hz),7.24-7.36 (1H, br), 7.38-7.49 (2H, m), 7.50-7.68 (1H, br), 8.11 (1H, d,J = 8.9 Hz), 9.00-9.45 (1H, br), 9.55-9.98 (1H, br), 10.50-12.10 (1H,br). 2 Hydrochloride 864

1H-NMR (DMSO-d6) δ ppm: 1.10-1.47 (6H, m), 1.54-1.80 (7H, m), 2.01-2.14(1H, m), 2.95-3.37 (4H, m), 4.00 (3H, s), 7.30 (1H, d, J = 8.3 Hz), 7.51(1H, d, J = 9.1 Hz), 7.73 (1H, brs), 7.95 (2H, d, J = 9.1 Hz), 9.39 (1H,brs), 9.90 (1H, brs), 11.80 (1H, brs). 2 Hydrochloride 865

1H-NMR (DMSO-d6) δ ppm: 1.03-1.44 (6H, m), 1.53-1.79 (7H, m), 1.97-2.09(1H, m), 2.92-3.06 (2H, m), 3.06-3.16 (1H, m), 3.16- 3.30 (1H, m),6.24-7.14 (1H, m), 7.36 (1H, dd, J = 2.1, 8.8 Hz), 7.49 (1H, dd, J =2.1, 8.8 Hz), 7.64 (1H, brs), 7.88 (1H, d, J = 8.8 Hz), 7.94 (1H, d, J =8.8 Hz), 8.00 (1H, d, J = 2.1 Hz), 9.10-9.39 (1H, brs), 9.63-9.87 (1H,brs). 2 Hydrochloride 866

1H-NMR (CDCl3) δ ppm: 0.75-1.19 (5H, m), 1.24-1.43 (3H, m), 1.45 (3H,s), 1.64-1.73 (1H, m), 1.73-1.82 (2H, m), 1.90-2.00 (1H, m), 2.45-2.54(1H, m), 2.72 (1H, d, J = 11.5 Hz), 2.83-2.92 (1H, m), 3.02 (1H, d, J =11.5 Hz), 7.26 (1H, dd, J = 2.1, 9.0 Hz), 7.37-7.47 (2H, m), 7.50 (1H,brs), 7.91 (1H, d, J = 9.0 Hz), 7.94-7.99 (2H, m), 8.30 (1H, s), 8.34(1H, s). — 867

1H-NMR (DMSO-d6) δ ppm: 1.15-1.45 (6H, m), 1.53-1.80 (7H, m), 1.97-2.10(1H, m), 2.94-3.09 (2H, m), 3.09-2.18 (1H, m), 3.18- 3.31 (1H, m),4.00-4.62 (1H, br), 7.16 (0.25H, s), 7.32-7.40 (2.5H, m), 7.53 (0.25H,s), 7.61- 7.72 (2H, m), 7.90 (1H, d, J = 8.8 Hz), 7.98 (1H, d, J = 9.0Hz), 9.10-9.45 (1H, br), 9.61- 9.90 (1H, br). 2 Hydrochloride 868

1H-NMR (DMSO-d6) δ ppm: 1.05-1.47 (6H, m), 1.55-1.80 (7H, m), 1.99-2.10(1H, m), 2.41-3.05 (2H, m), 3.05-3.16 (1H, m), 3.16- 3.30 (1H, m),3.75-4.60 (4H, m), 7.45 (1H, dd, J = 2.0, 8.8 Hz), 7.57 (1H, s), 7.67(1H, s), 7.90 (1H, d, J = 8.9 Hz), 8.48 (1H, s), 9.10- 9.40 (1H, br),9.61-9.90 (1H, br). 3 Hydrochloride 869

1H-NMR (DMSO-d6) δ ppm: 1.05-1.45 (6H, m), 1.54-1.80 (7H, m), 1.96-2.07(1H, m), 2.93-3.04 (1H, m), 3.04-3.16 (2H, m), 3.18- 3.32 1H, m),4.23-4.51 (1H, br), 7.46-7.50 (1H, m), 7.58-7.67 (3H, m), 7.97-8.04 (1H,m), 8.08-8.14 (1H, m), 9.03-9.25 (1H, br), 9.51- 9.75 (1H, br). 2Hydrochloride 870

1H-NMR (DMSO-d6) δ ppm: 1.08-1.45 (6H, m), 1.52-1.80 (7H, m), 1.99-2.10(1H, m), 2.96-3.17 (3H, m), 3.17-3.30 (1H, m), 4.45- 4.55 (1H, br), 7.16(1H, dd, J = 1.7, 12.3 Hz), 7.48 (1H, s), 7.51-7.64 (2H, m), 7.98 (2H,d, J = 8.2 Hz), 9.15-9.36 (1H, br), 9.70-9.90 (1H, br). 2 Hydrochloride871

1H-NMR (CDCl3) δ ppm: 1.00-1.15 (4H, m), 1.15-1.52 (7H, m), 1.57-1.68(1H, m), 1.68- 1.79 (3H, m), 2.34-2.42 (1H, m), 2.69 (1H, d, J = 11.3Hz), 2.77-2.86 (1H, m), 2.88 (1H, d, J = 11.3 Hz), 4.28 (2H, dt, J =4.1, 13.1 Hz), 6.15 (1H, tt, J = 4.1, 55.2 Hz), 7.10 (1H, d, J = 2.5Hz), 7.14 (1H, dd, J = 2.6, 8.9 Hz), 7.27 (1H, dd, J = 2.1, 8.7 Hz),7.41 (1H, d, J = 2.0 Hz), 7.63-7.72 (2H, m). — 872

1H-NMR (CDCl3) δ ppm: 1.00-1.15 (4H, m), 1.20-1.70 (8H, m), 1.70-1.88(3H, m), 2.39- 2.48 (1H, m), 2.70 (1H, d, J = 11.4 Hz), 2.80- 2.89 (1H,m), 2.93 (1H, d, J = 11.4 Hz), 4.29 (2H, dt, J = 4.2, 13.1 Hz), 6.15(1H, tt, J = 4.1, 55.2 Hz), 7.03-7.11 (2H, m), 7.16 (1H, dd, J = 2.1,8.7 Hz), 7.33 (1H, d, J = 2.0 Hz), 7.65- 7.74 (2H, m). — 873

1H-NMR (DMSO-d6) δ ppm: 0.90-1.06 (1H, m), 1.06-1.64 (17H, m), 1.64-1.74(1H, m), 1.80-1.83 (1H, m), 2.50-2.62 (1H, m), 2.71 (1H, d, J = 11.9Hz), 2.86 (1H, d, J = 11.9 Hz), 2.92-3.02 (1H, m), 4.78 (2H, s), 6.48(2H, s), 6.73 (1H, d, J = 8.6 Hz), 6.83 (1H, d, J = 2.2 Hz), 6.91 (1H,dd, J = 2.3, 8.6 Hz), 9.37-11.61 (1H, br). Fumarate

TABLE 96 absolute configuration

Example R⁴ NMR Salt 874

1H-NMR (DMSO-d6) δ ppm: 0.96-1.10 (1H, m), 1.10-1.25 (1H, m), 1.26-1.41(4H, m), 1.47-1.78 (7H, m), 1.94-2.05 (1H, m), 2.56 (3H, s), 2.84 (1H,d, J = 12.4 Hz), 2.90-3.02 (2H, m), 3.23-3.35 (1H, m), 7.15 (1H, d, J =7.6 Hz), 7.22-7.33 (2H, m), 7.68 (1H, d, J = 7.9 Hz), 8.91-9.09 (1H,brm), 9.54-9.70 (1H, brm). Hydrochloride 875

1H-NMR (DMSO-d6) δ ppm (80° C.): 1.03- 1.46 (6H, m), 1.51-1.78 (7H, m),2.01-2.11 (1H, m), 2.53 (3H, s), 2.88 (1H, d, J = 12.4 Hz), 2.97-3.08(1H, m), 3.10-3.25 (2H, m), 7.05 (1H, s), 7.13 (1H, d, J = 8.4 Hz),7.60- 7.68 (2H, m), 9.20 (1H, brs), 9.70 (1H, brs). Hydrochloride 876

1H-NMR (DMSO-d6) δ ppm: 0.95-1.40 (6H, m), 1.40-1.78 (7H, m), 1.95-2.05(1H, m), 2.85 (1H, d, J = 12.5 Hz), 2.90-3.00 (1H, m), 3.03 (1H, d, J =12.5 Hz), 3.28-3.44 (1H, m), 7.26 (2H, d, J = 7.0 Hz), 7.64 (1H, dd, J =4.0, 5.2 Hz), 7.86 (1H, d, J = 5.4 Hz), 9.07 (1H, brs), 9.64 (1H, brs).Hydrochloride 877

1H-NMR (DMSO-d6) δ ppm: 0.97-1.45 (6H, m), 1.45-1.80 (7H, m), 1.94-2.09(1H, m), 2.88 (1H, d, J = 12.5 Hz), 2.93-3.05 (2H, m), 3.26- 3.45 (1H,m), 7.28 (1H, d, J = 8.2 Hz), 7.50 (1H, d, J = 8.2 Hz), 7.64 (1H, d, J =5.4 Hz), 7.88 (1H, d, J = 5.4 Hz), 9.06 (1H, brs), 9.59 (1H, brs).Hydrochloride 878

1H-NMR (DMSO-d6) δ ppm: 0.90-1.79 (13H, m), 1.35-2.06 (1H, m), 2.75-3.05(4H, m), 3.94 (3H, s), 6.94 (1H, d, J = 7.9 Hz), 7.18 (1H, d, J = 7.9Hz), 7.55 (1H, d, J = 5.4 Hz), 7.71 (1H, d, J = 5.4 Hz), 8.80 (1H, brs),9.21 (1H, brs). Hydrochloride

TABLE 97 absolute configuration

Example R⁴ NMR Salt 879

1H-NMR (DMSO-d6) δ ppm: 0.97-1.10 (1H, m), 1.10-1.41 (5H, m), 1.50-1.78(7H, m), 1.94-2.05 (1H, m), 2.44 (3H, s), 2.75-3.09 (3H, m), 3.09-3.30(1H, m), 6.58 (1H, brs), 6.98 (1H, d, J = 7.2 Hz), 7.19 (1H, t, J = 7.8Hz), 7.31 (1H, d, J = 7.8 Hz), 9.00 (1H, brs), 9.59 (1H, brs).Hydrochloride 880

1H-NMR (DMSO-d6) δ ppm: 1.00-1.43 (6H, m), 1.44-1.78 (7H, m), 1.90-2.07(1H, m), 2.42 (3H, d, J = 0.9 Hz), 2.75-3.30 (4H, m), 3.48- 4.50 (1H,br), 6.54 (1H, s), 7.04 (1H, brs), 7.30 (1H, brs), 7.48 (1H, d, J = 8.6Hz), 9.11 (1H, brs), 9.70 (1H, brs). 2 Hydrochloride 881

1H-NMR (DMSO-d6) δ ppm: 0.99-1.15 (1H, m), 1.15-1.42 (5H, m), 1.47-1.77(7H, m), 1.93-2.05 (1H, m), 2.75-3.18 (3H, m), 3.27 (1H, brs), 7.08 (1H,brs), 7.22 (1H, brs), 8.14 (1H, s), 9.00 (1H, brs), 9.67 (1H, brs).Hydrochloride 882

1H-NMR (CDCl3) δ ppm: 0.75-1.14 (5H, m), 1.14-1.40 (3H, m), 1.42 (3H,s), 1.56-1.68 (2H, m), 1.68-1.79 (2H, m), 2.20-2.30 (1H, m), 2.65 (1H,d, J = 11.1 Hz), 2.74-2.85 (2H, m), 3.99 (3H, s), 6.61 (1H, d, J = 1.7Hz), 6.70 (1H, d, J = 2.1 Hz), 6.95 (1H, d, J = 1.7 Hz), 7.59 (1H, d, J= 2.1 Hz). — 883

1H-NMR (DMSO-d6) δ ppm: 1.01-1.42 (6H, m), 1.49-1.68 (6H, m), 1.68-1.78(1H, m), 1.95-2.05 (1H, m), 2.80-2.95 (2H, m), 3.01- 3.10 (1H, m),3.10-3.24 (1H, m), 6.50-7.80 (4H, m), 8.10 (1H, d, J = 2.1 Hz), 9.13(1H, brs), 9.71 (1H, brs). 2 Hydrochloride 884

1H-NMR (DMSO-d6) δ ppm: 1.00-1.41 (6H, m), 1.45-1.67 (6H, m), 1.67-1.77(1H, m), 1.92-2.03 (1H, m), 2.80-2.94 (2H, m), 3.01- 3.10 (1H, m),3.10-3.25 (1H, m), 3.65-4.00 (1H, br), 7.05 (1H, d, J = 2.1 Hz), 7.18(1H, d, J = 1.7 Hz), 7.43 (1H, d, J = 1.7 Hz), 8.12 (1H, d, J = 2.1 Hz),9.10 (1H, brs), 9.60 (1H, brs). 2 Hydrochloride 885

1H-NMR (DMSO-d6) δ ppm: 0.92-1.07 (1H, m), 1.07-1.88 (13H, m), 2.60-3.01(4H, m), 3.10-4.92 (2H, br), 6.45 (3H, s), 7.35 (1H, dd, J = 2.1, 8.9Hz), 7.54 (1H, d, J = 2.0 Hz), 7.68 (1H, d, J = 8.9 Hz), 8.04 (1H, d, J= 0.8 Hz). Fumarate 886

1H-NMR (CDCl3) δ ppm: 0.96-1.12 (4H, m), 1.16-1.44 (6H, m), 1.55-1.80(5H, m), 2.20- 2.30 (1H, m), 2.62 (1H, d, J = 11.2 Hz), 2.75- 2.85 (2H,m), 7.04 (1H, dd, J = 1.8, 11.8 Hz), 7.15 (1H, d, J = 1.8 Hz), 7.42 (1H,d, J = 2.5 Hz). — 887

1H-NMR (CDCl3) δ ppm: 0.96-1.15 (4H, m), 1.15-1.39 (3H, m), 1.42 (3H,s), 1.55-1.69 (3H, m), 1.69-1.80 (2H, m), 2.23-2.34 (1H, m), 2.65 (1H,d, J = 11.1 Hz), 2.75-2.85 (2H, m), 4.01 (3H, s), 6.76 (1H, d, J = 1.17Hz), 6.97 (1H, d, J = 1.17 Hz), 7.38 (1H, s). — 888

1H-NMR (DMSO-d6) δ ppm: 0.99-1.42 (6H, m), 1.50-1.78 (7H, m), 1.72-2.05(1H, m), 2.75-3.11 (3H, m), 3.16-3.40 (1H, br), 4.95- 6.80 (1H, br),6.95-7.11 (2H, m), 7.12-7.21 (1.25H, m), 7.33 (0.5H, s), 7.51 (0.25H,s), 8.08 (1H, brs), 9.05 (1H, brs), 9.64 (1H, brs). 2 Hydrochloride 889

1H-NMR (CDCl3) δ ppm: 0.99-1.12 (4H, m), 1.20-1.43 (7H, m), 1.62-1.83(4H, m), 2.34- 2.42 (1H, m), 2.70 (1H, d, J = 11.5 Hz), 2.76- 2.85 (1H,m), 2.91 (1H, d, J = 11.5 Hz), 3.92 (3H, s), 6.45 (1H, d, J = 1.4 Hz),6.80-6.83 (1H, m), 7.45 (1H, d, J = 0.9 Hz). — 890

1H-NMR (CDCl3) δ ppm: 1.01-1.15 (4H, m), 1.20-1.45 (7H, m), 1.67-1.90(4H, m), 2.44- 2.53 (1H, m), 2.77-2.87 (2H, m), 2.98 (1H, d, J = 11.9Hz), 6.74 (1H, dd, J = 1.6, 11.5 Hz), 6.90-6.94 (1H, m), 7.43 (1H, d, J= 0.9 Hz). —

TABLE 98 absolute configuration

Example R⁴ NMR Salt 891

1H-NMR (CDCl3) δ ppm: 0.83-1.43 (26H, m), 1.52 (3H, s), 1.55-1.91 (7H,m), 2.34-2.61 (2H, m), 2.80-3.00 (2H, m), 6.69-6.84 (3H, m), 7.24 (1H,d, J = 3.2 Hz). — 892

1H-NMR (CDCl3) δ ppm: 0.76-1.40 (26H, m), 1.52 (3H, s), 1.56-1.95 (7H,m), 2.36-2.64 (2H, m), 2.80-3.01 (2H, m), 3.88 (3H, s), 6.54 (1H, d, J =8.1 Hz), 6.69 (1H, d, J = 3.1 Hz), 6.73 (1H, d, J = 8.1 Hz), 7.24 (1H,d, J = 3.1 Hz). — 893

1H-NMR (CDCl3) δ ppm: 0.98-1.17 (23H, m), 1.17-1.40 (3H, m), 1.42 (3H,s), 1.55-1.66 (2H, m), 1.66-1.76 (2H, m), 1.84 (3H, quint, J = 7.5 Hz),2.27-2.38 (1H, m), 2.72 (1H, d, J = 11.2 Hz), 2.77-2.85 (2H, m), 6.47(1H, d, J = 3.4 Hz), 7.27 (1H, d, J = 3.4 Hz), 7.61 (1H, d, J = 2.4 Hz),8.06 (1H, d, J = 2.4 Hz). — 894

1H-NMR (CDCl3) δ ppm: 0.90-1.40 (26H, m), 1.43 (3H, s), 1.59-1.80 (4H,m), 1.95-2.06 (3H, m), 2.30-2.39 (1H, m), 2.58 (1H, d, J = 11.3 Hz),2.79-2.89 (2H, m), 6.98 (1H, d, J = 1.5, 8.5 Hz), 7.31 (1H, s), 7.34(1H, d, J = 0.6 Hz), 7.52 (1H, d, J = 8.5 Hz). —

TABLE 99 absolute configuration

Example R⁴ NMR Salt 895

1H-NMR (DMSO-d6) δ ppm: 0.77-0.92 (1H, m), 0.95 (3H, s), 1.08-1.35 (3H,m), 1.40 (3H, s), 1.47 -1.58 (2H, m), 1.58-1.82 (3H, m), 2.27- 2.48 (2H,m), 2.60-2.85 (2H, m), 6.47 (1H, brs), 6.58-6.65 (1H, m), 6.81 (1H, dd,J = 8.3, 10.9 Hz), 7.30 (1H, t, J = 2.6 Hz), 11.47 (1H, s). — 896

1H-NMR (CDCl3) δ ppm: 0.77-0.99 (4H, m), 1.08-1.90 (11H, m), 2.21 -2.46(2H, m), 2.58- 2.85 (2H, m), 3.86 (3H, s), 6.38 (1H, brs), 6.47-6.63(2H, m), 7.13 (1H, t, J = 2.6 Hz), 11.07 (1H, s). — 897

1H-NMR (DMSO-d6) δ ppm: 0.91-1.08 (1H, m), 1.08-1.60 (11H, m), 1.61-1.72(1H, m), 1.78-1.90 (1H, m), 2.60-2.71 (1H, m), 2.75 (1H, d, J = 11.7Hz), 2.90-3.05 (2H, m), 6.39 (1H, dd, J = 1.8, 3.4 Hz), 6.47 (1H, s),7.42- 7.49 (1H, m), 7.73 (1H, d, J = 2.0 Hz), 7.98 (1H, d, J = 2.2 Hz),8.18-10.97 (2H, br), 11.59 (1H, s). ½ Fumarate 898

1H-NMR (DMSO-d6) δ ppm: 0.81-1.02 (4H, m), 1.10-1.36 (6H, n), 1.36-2.05(5H, m), 2.25- 2.35 (1H, m), 2.57 (1H, d, J = 11.0 Hz), 2.62- 2.70 (1H,m), 2.75 (1H, d, J = 11.0 Hz), 6.91 (1H, dd, J = 1.7, 8.6 Hz), 7.03 (1H,s), 7.27 (1H, d, J = 0.6 Hz), 7.55 (1H, d, J = 8.6 Hz) 11.93-12.33 (1H,br). —

TABLE 100 absolute configuration

Example R⁴ NMR Salt 899

1H-NMR (CDCl3) δ ppm: 0.75-1.13 (5H, m), 1.25-1.45 (3H, m), 1.48 (3H,s), 1.62-1.85 (3H, m), 2.08-2.19 (1H, m), 2.66-2.78 (2H, m), 2.85-2.94(1H, m), 3.27 (1H, d, J = 11.9 Hz), 3.85 (3H, s), 6.46 (1H, d, J = 3.5Hz), 6.63 (1H, d, J = 5.4 Hz), 7.06 (1H, d, J = 3.5 Hz), 8.20 (1H, d, J= 5.4 Hz). — 900

1H-NMR (DMSO-d6) δ ppm: 0.91-1.62 (11H, m), 1.62-1.84 (2H, m), 1.82-1.95(1H, m), 2.65-2.83 (2H, m), 2.99-3.10 (2H, m), 3.79 (3H, s), 6.41 (1H,d, J = 3.4 Hz), 6.48 (2H, s), 7.50 (1H, d, J = 3.4 Hz), 7.76 (1H, d, J =2.2 Hz), 8.04 (1H, d, J = 2.2 Hz), 8.35-11.00 (2H, br) Fumarate

TABLE 101 absolute configuration

Example R⁴ NMR Salt 901

1H-NMR (DMSO-d6) δ ppm: 0.86-1.01 (1H, m), 1.12-1.40 (5H, m), 1.51-1.76(7H, m), 1.72- 2.10 (3H, m), 2.67-2.81 (2H, m), 2.81-3.00 (5H, m),3.05-3.20 (1H, m), 6.65-7.10 (2H, m), 7.21 (1H, d, J = 8.4 Hz),9.03-9.20 (1H, m), 9.59-9.77 (1H, m). 2 Hydrochloride 902

1H-NMR (DMSO-d6) δ ppm: 0.88-1.04 (1H, m), 1.15-1.41 (5H, m), 1.48-1.80(7H, m), 1.90-2.10 (3H, m), 2.65-3.05 (7H, m), 3.05- 3.22 (1H, m),4.90-6.25 (1H, br), 6.94 (1H, s), 7.11 (1H, s), 9.21 (1H, brs), 9.70(1H, brs). 2 Hydrochloride 903

1H-NMR (DMSO-d6) δ ppm: 0.93-1.22 (2H, m), 1.22-1.43 (4H, m), 1.43-1.79(7H, m), 1.90-2.10 (1H, m), 2.58-3.40 (6H, m), 4.52 (2H, t, J = 8.6 Hz),5.30-6.20 (1H, br), 6.50- 7.45 (3H, m), 8.65-9.38 (1H, br), 9.38-9.92(1H, br). 2 Hydrochloride 904

1H-NMR (DMSO-d6) δ ppm: 0.96-1.13 (1H, m), 1.13-1.42 (5H, m), 1.49-1.66(6H, m), 1.66-1.77 (1H, m), 1.93-2.05 (1H, m), 2.74- 2.90 (2H, m), 2.98(1H, d, J = 12.5 Hz), 3.08- 3.20 (1H, m), 4.35-4.68 (1H, br), 6.95 (1H,dd, J = 2.0, 8.6 Hz), 7.26 (1H, d, J = 2.0 Hz), 7.36 (1H, d, J = 8.6Hz), 8.98-9.20 (1H, br), 9.60- 9.85 (1H, br). 2 Hydrochloride

TABLE 102 absolute configuration

Example R⁴ NMR Salt 905

1H-NMR (CDCl3) δ ppm: 0.75-1.04 (2H, m), 1.04-1.13 (21H, m), 1.15-1.37(6H, m), 1.38 (3H, s, 1.52-1.75 (4H, m), 2.12-2.20 (1H, m), 2.58 (1H, d,J = 11.1 Hz), 2.69-2.78 (2H, m), 6.76-6.81 (2H, m), 6.92-6.97 (2H, m).906

1H-NMR (CDCl3) δ ppm: 0.88-1.14 (23H, m), 1.16-1.37 (6H, m), 1.38 (3H,s), 1.60-1.77 (4H, m), 2.20-2.29 (1H, m), 2.57 (1H, d, J = 11.3 Hz),2.72-2.82 (2H, m), 6.60-6.65 (2H, m), 6.65-6.70 (1H, m), 7.07-7.14 (1H,m). 907

1H-NMR (CDCl3) δ ppm: 0.75-1.15 (23H, m), 1.17-1.40 (9H, m), 1.52-1.75(4H, m), 2.10- 2.17 (1H, m), 2.55 (1H, d, J = 11.1 Hz), 2.70- 2.77 (2H,m), 6.69-6.74 (1H, m), 6.78-6.87 (2H, m). 908

1H-NMR (CDCl3) δ ppm: 0.81-1.38 (29H, m), 1.39 (3H, s), 1.58-1.76 (4H,m), 2.23-2.32 (1H, m), 2.61 (1H, d, J = 11.2 Hz), 2.72-2.82 (2H, m),4.79 (2H, s), 7.02-7.08 (2H, m), 7.24- 7.30 (2H, m). 909

1H-NMR (CDCl3) δ ppm: 0.75-1.35 (29H, m), 1.37 (3H, s), 1.62-1.78 (4H,m), 2.22-2.30 (1H, m), 2.60 (1H, d, J = 11.4 Hz), 2.71-2.85 (2H, m),5.30 (2H, s), 6.72 (1H, dd, J = 2.0, 12.0 Hz), 6.86 (1H, J = 2.0, 8.2Hz), 7.44 (1H, t, J = 8.4 Hz). 910

1H-NMR (CDCl3) δ ppm: 0.75-1.39 (32H, m), 1.53-1.75 (4H, m), 2.10-2.17(1H, m), 2.56 (1H, d. J = 11.1 Hz), 2.68-2.77 (2H, m), 6.80 (1H, d, J =8.6 Hz), 6.84 (1H, dd, J = 2.4, 8.6 Hz), 7.08 (1H, d, J = 2.4 Hz). 911

1H-NMR (CDCl3) δ ppm: 0.85-1.09 (23H, m), 1.09-1.36 (3H, m), 1.37 (3H,s), 1.50-1.75 (4H, m), 2.11-2.19 (1H, m), 2.57 (1H, d, J = 11.1 Hz),2.67-2.77 (2H, m), 4.95 (2H, s), 6.67 (1H, d, J = 2.5 Hz), 6.82 (1H, d,J = 8.5 Hz), 6.91 (1H, dd, J = 2.5, 8.5 Hz).

TABLE 103 absolute configuration

Example R⁴ NMR Salt 912

1H-NMR (CDCl3) δ ppm: 0.92-1.06 (1H, m), 1.09 (3H, s), 1.12-1.37 (3H,m), 1.40 (3H, s), 1.55-1.66 (2H, m), 1.66-1.78 (2H, m), 2.15- 2.25 (1H,m), 2.57-2.65 (1H, m), 2.69-2.83 (2H, m), 3.15-4.30 (2H, br), 6.72-6.79(2H, m), 6.95-7.01 (2H, m). — 913

1H-NMR (DMSO-d6) δ ppm: 0.82-1.00 (4H, m), 1.09-1.35 (6H, m), 1.40-1.52(1H, m), 1.52-1.70 (4H, m), 2.12-2.25 (1H, m), 2.45- 2.55 (1H, m),2.55-2.65 (1H, m), 2.66 (1H, d, J = 11.0 Hz), 6.40-6.51 (3H, m),7.00-7.10 (1H, m), 9.21 (1H, s). — 914

1H-NMR (DMSO-d6) δ ppm: 0.90-1.05 (1H, m), 1.05-1.38 (5H, m), 1.38-1.62(6H, m), 1.64-1.74 (1H, m), 1.62-1.94 (1H, m), 2.53- 2.62 (1H, m), 2.70(1H, d, J = 12.0 Hz), 2.86 (1H, d, J = 12.0 Hz), 2.95-3.06 (1H, m), 3.74(3H, s), 4.45 (2H, s), 4.65-5.60 (1H, br), 6.46 (1H, s), 6.87 (1H, d, J= 8.6 Hz), 6.94 (1H, dd, J = 2.5, 8.6 Hz), 7.15 (1H, d, J = 2.2 Hz),8.59-10.40 (1H, br). ½ Fumarate 915

1H-NMR (DMSO-d6) δ ppm: 0.82-0.99 (4H, m), 1.05-1.32 (6H, m), 1.41-1.50(1H, m), 1.50-1.65 (3H, m), 2.05-2.14 (1H, m), 2.47 (1H, d, J = 10.8Hz), 2.53-2.62 (2H, m), 2.95- 3.65 (1H, br), 6.67-6.72 (1H, m),6.79-6.87 (2H, m), 8.65-10.50 (1H, m). — 916

1H-NMR (CDCl3) δ ppm: 0.85-1.10 (5H, m), 1.15-1.42 (6H, m), 1.56-2.05(5H, m), 2.25- 2.15 (1H, m) 2.56-2.65 (1H, m), 2.72-2.84 (2H, m), 4.64(2H, s), 7.04-7.10 (2H, m), 7.25- 7.32 (2H, m). — 917

1H-NMR (CDCl3) δ ppm: 0.95-1.44 (11H, m), 1.44-2.20 (5H, m), 2.25-2.35(1H, m), 2.61 (1H, d, J = 11.4 Hz), 2.72-2.86 (2H, m), 4.69 (2H, s),6.75 (1H, dd, J = 2.0, 12.1 Hz), 6.83 (1H, dd, J = 2.0, 8.1 Hz), 7.29(1H, t, J = 8.4 Hz). — 918

1H-NMR (CDCl3) δ ppm: 0.90-1.11 (4H, m), 1.14-1.42 (6H, m), 1.53-1.77(4H, m), 2.12- 2.21 (1H, m), 2.57 (1H, d, J = 11.2 Hz), 2.67- 2.80 (2H,m), 2.81-3.38 (2H, br), 6.89-6.97 (2H, m), 7.07 (1H, dd, J = 0.5, 1.9Hz). — 919

1H-NMR (DMSO-d6) δ ppm: 0.78-0.93 (1H, m), 0.95 (3H, s), 1.04-1.32 (6H,m), 1.37-1.66 (5H, m), 2.05-2.14 (1H, m), 2.45-2.62 (3H, m), 4.43 (2H,s), 4.65-5.20 (1H, br), 6.65 (1H, d, J = 8.4 Hz), 6.74 (1H, dd, J = 2.5,8.4 Hz), 7.03 (1H, d, J = 2.5 Hz), 8.81-9.28 (1H, br). —

TABLE 104 absolute configuration

Example R⁵ R⁶ R⁷ R⁸ R⁹ NMR Salt 920 —CH3 —H —H —H —H 1H-NMR (DMSO-d6) δppm: 0.88-1.03 (1H, m), 1.10-1.25 (1H, m), 1.25- 1.40 (4H, m), 1.45-1.66(6H, m), 1.67-1.89 (1H, m), 1.92-2.03 (1H, m), 2.26 (3H, m), 2.65 (1H,d, J = 12.5 Hz), 2.80 (1H, d, J = 12.5 Hz), 2.88-3.00 (1H, m), 3.15-3.28(1H, m), 7.06-7.17 (2H, m), 7.19-7.26 (2H, m), 9.04 (1H, brs), 9.58 (1H,brs). Hydrochloride 921 —CH3 —CH3 —H —H —H 1H-NMR (DMSO-d6) δ ppm:0.87-1.02 (1H, m), 1.10-1.24 (1H, m), 1.24- 1.40 (4H, m), 1.40-1.64 (6H,m), 1.67-1.77 (1H, m), 1.95-2.04 (1H, m), 2.21 (3H, s), 2.22 (3H, s),2.59 (1H, d, J = 12.5 Hz), 2.82 (1H, d, J = 12.5 Hz), 2.86-2.95 (1H, m),3.15- 3.37 (1H, m), 6.97-7.03 (2H, m), 7.07-1.15 (1H, m), 9.11 (1H,brs), 9.65 (1H, brs). Hydrochloride 922 —H —F —CN —H —H 1H-NMR (DMSO-d6)δ ppm: 1.22-1.65 (10H, m), 1.65-1.84 (2H, m), 1.90-2.00 (1H, m), 2.10-2.20 (1H, m), 3.38-3.61 (4H, m), 3.78 (1H, d, J = 14.5 Hz), 6.83 (1H,dd, J = 2.3, 8.9 Hz), 6.97 (1H, dd, J = 2.0, 13.7 Hz), 7.65 (1H, t, J =8.5 Hz), 8.93-9.15 (1H, m), 9.51- 9.71 (1H, m). 2 Hydrochloride 923 —H—H —OCF3 —H —H 1H-NMR (DMSO-d6) δ ppm: 1.00-1.15 (1H, m), 1.15-1.41 (5H,m), 1.50- 1.67 (6H, m), 1.67-1.77 (1H, m), 1.95-2.05 (1H, m), 2.81-2.95(2H, m), 3.01 (1H, d, J = 12.5 Hz), 3.11-3.25 (1H, m), 5.42- 6.30 (1H,br), 7.20-7.27 (2H, m), 7.31-7.37 (2H, m), 9.02-9.20 (1H, brm),9.60-9.80 (1H, brm). 2 Hydrochloride 924 —H —F —OCF3 —H —H 1H-NMR(DMSO-d6) δ ppm: 1.04-1.20 (1H, m), 1.20-1.41 (5H, m), 1.40- 1.78 (7H,m), 1.96-2.06 (1H, m), 2.85-3.11 (3H, m), 3.15-3.28 (1H, m), 5.10-6.50(1H, br), 7.00- 7.15 (1H, m), 7.22-7.29 (1H, m), 7.47-7.54 (1H, m), 9.09(1H, brs), 9.71 (1H, brs). 2 Hydrochloride 925 —H —H —OCHF2 —H —H 1H-NMR(DMSO-d6) δ ppm: 0.98-1.11 (1H, m), 1.11-1.25 (1H, m), 1.25- 1.40 (4H,m), 1.48-1.65 (6H, m), 1.65-1.76 (1H, m), 1.92-2.03 (1H, m), 2.75-2.90(2H, m), 2.99 (1H, d, J = 12.8 Hz), 3.10-3.23 (1H, m), 4.85- 5.90 (1H,br), 7.01 (0.25H, s), 7.13-7.22 (4.5H, m), 7.38 (0.25H, s), 9.06 (1H,brs), 9.63 (1H, brs). 2 Hydrochloride 926 —H —Cl —OCHF2 —H —H 1H-NMR(DMSO-d6) δ ppm: 1.02-1.42 (6H, m), 1.50-1.66 (6H, m), 1.66- 1.77 (1H,m), 1.95-2.05 (1H, m), 2.81-2.94 (2H, m), 3.02 (1H, d, J = 12.5 Hz),3.10-3.23 (1H, m), 3.88-4.25 (1H, br), 7.15 (1H, dd, J = 2.6, 8.8 Hz),7.24 (1H, t, J = 73.3 Hz), 7.32 (1H, d, J = 2.6 Hz), 7.34 (1H, d, J =8.8 Hz), 9.05-9.22 (1H, m), 9.62- 9.80 (1H, m). 2 Hydrochloride 927 —H—OCHF2 —H —H —H 1H-NMR (DMSO-d6) δ ppm: 1.02-1.16 (1H, m), 1.18-1.41(5H, m), 1.50- 1.67 (6H, m), 1.67-1.78 (1H, m), 1.96-2.06 (1H, m),2.84-2.97 (2H, m), 3.04 (1H, d, J = 12.5 Hz), 3.11-3.25 (1H, m), 6.89(1H, s), 6.96 (1H, dd, J = 2.1, 8.1 Hz), 7.00 (1H, d, J = 8.1 Hz), 7.27(1H, t, J = 4.1 Hz), 7.39 (1H, t, J = 8.1 Hz), 8.30-9.30 (2H, br),9.69-9.89 (1H, br). 2 Hydrochloride 928 —H —OCHF2 —Cl —H —H 1H-NMR(DMSO-d6) δ ppm: 1.04-1.40 (6H, m), 1.50-1.69 (6H, m), 1.69- 1.79 (1H,m), 1.92-2.04 (1H, m), 2.78-2.89 (1H, m), 2.89-3.06 (2H, m), 3.15-3.27(1H, m), 7.01- 7.08 (2H, m), 7.32 (1H, t, J = 73.3 Hz), 7.54 (1H, d, J =8.4 Hz), 8.81-9.11 (1H, m), 9.40-9.69 (1H, m). Hydrochloride 929 —H—OCHF2 —F —H —H 1H-NMR (DMSO-d6) δ ppm: 1.00-1.40 (8H, m), 1.47-1.65(8H, m), 1.67- 1.77 (1H, m), 1.90-2.00 (1H, m), 2.70-2.80 (1H, m), 2.87(1H, d, J = 12.5 Hz), 2.96 (1H, d, J = 12.5 Hz), 3.10-3.24 (1H, m),7.02-7.11 (2.25H, m), 7.27 (0.5H, s), 7.37 (1H, dd, J = 8.8, 10.5 Hz),7.46 (0.25H, s), 8.80-9.00 (1H, br), 9.39-9.58 (1H, br). Hydrochloride930 —H —CN —OCHF2 —H —H 1H-NMR (DMSO-d6) δ ppm: 1.03-1.15 (1H, m),1.17-1.41 (5H, m), 1.48- 1.82 (7H, m), 1.93-2.05 (1H, m), 2.82-2.91 (1H,m), 2.94 (1H, d, J = 12.7 Hz), 3.01 (1H, d, J = 12.7 Hz), 3.08-3.25 (1H,m), 4.00-4.60 (1H, br), 7.39 (1H, t, J = 72.6 Hz), 7.42 (1H, d, J = 8.9Hz), 7.51 (1H, dd, J = 2.7, 9.0 Hz), 7.69 (1H, d, J = 2.7 Hz), 8.90-9.10(1H, br), 9.40- 9.65 (1H, br). 2 Hydrochloride 931 —H —F —OCHF2 —F —H1H-NMR (DMSO-d6) δ ppm: 1.08-1.42 (6H, m), 1.42-1.80 (7H, m), 1.96- 2.07(1H, m), 2.90-3.00 (1H, m), 3.05 (1H, d, J = 13.0 Hz), 3.10 (1H, d, J =3.0 Hz), 3.17-3.29 (1H, m), 3.55-3.85 (1H, br), 6.97-7.06 (2.25H, m),7.19 (0.5H, s), 7.37 (0.25H, s), 8.90-9.07 (1H, br), 9.51-9.70 (1H, br).2 Hydrochloride 932 —H —H —OCH2CHF2 —H —H 1H-NMR (DMSO-d6) δ ppm:0.98-1.80 (13H, m), 1.91-2.14 (1H, m), 2.61-3.50 (4H, m), 4.20- 4.40(2H, m), 4.61-6.20 (1H, br), 6.39 (1H, tt, J = 3.4, 54.5 Hz), 6.85-7.65(4H, brm), 8.84-10.20 (2H, br). 2 Hydrochloride 933 —H —F —OCH2CHF2 —H—H 1H-NMR (CDCl3) δ ppm: 0.95-1.09 (4H, m), 1.15- 1.44 (7H, m),1.57-1.78 (4H, m), 2.13-2.22 (1H, m), 2.56 (1H, d, J = 11.1 Hz),2.70-2.79 (2H, m), 4.21 (2H, dt, J = 4.2, 13.1 Hz), 6.08 (1H, tt, J =4.2, 55.1 Hz), 6.77-6.83 (1H, m), 6.84-6.95 (2H, m). — 934 —H —Cl—OCH2CHF2 —H —H 1H-NMR (CDCl3) δ ppm: 0.93-1.10 (4H, m), 1.15- 1.41 (7H,m), 1.53-1.77 (4H, m), 2.14-2.23 (1H, m), 2.57 (1H, d, J = 11.0 Hz),2.68-2.79 (2H, m), 4.20 (2H, dt, J = 4.2, 13.0 Hz), 6.12 (1H, tt, J =4.2, 55.1 Hz), 6.87 (1H, d, J = 8.7 Hz), 6.96 (1H, dd, J = 2.5, 8.7 Hz),7.13 (1H, d, J = 2.5 Hz). — 935 —H —CH3 —OCHF2 —H —H 1H-NMR (DMSO-d6) δppm: 0.96-1.10 (1H, m), 1.12-1.40 (5H, m), 1.47- 1.63 (6H, m), 1.67-1.76(1H, m), 1.90-2.01 (1H, m), 2.21 (3H, m), 2.70- 2.87 (2H, m), 2.96 (1H,d, J = 12.1 Hz), 3.07-3.22 (1H, m), 4.40-6.50 (1H, br), 6.94 (0.25H, s),6.97- 7.03 (1H, m), 7.03-7.08 (1H, m), 7.09-7.15 (1.5H, m), 7.31 (0.25H,s), 9.01 (1H, brs), 9.56 (1H, brs). 2 Hydrochloride 936 —H —OCH3 —OCHF2—H —H 1H-NMR (DMSO-d6) δ ppm: 1.02-1.40 (6H, m), 1.50-1.79 (7H, m),1.96- 2.06 (1H, m), 2.78-2.95 (2H, m), 2.98-3.22 (2H, m), 3.82 (3H, s),6.75 (1H, d, J = 7.8 Hz), 6.80- 6.93 (1.25H, m), 7.01 (0.5H, s),7.11-7.21 (1.25H, m), 7.21-7.75 (1H, br), 9.14 (1H, brs), 9.77 (1H,brs). 2 Hydrochloride

TABLE 105 absolute configuration

Example R⁴ NMR Salt 937

1H-NMR (DMSO-d6) δ ppm: 1.15-1.60 (10H, m), 1.60-1.86 (2H, m), 1.95-2.15(2H, m), 2.47 (3H, s), 3.37 (1H, d, J = 14.2 Hz), 3.41-3.66 (2H, m),3.88 (1H, d, J = 14.2 Hz), 5.32-7.05 (1.5H, br), 7.18 (1H, d, J = 9.2Hz), 7.36 (1H, d, J = 9.2 Hz), 7.45-9.40 (1.5H, br). Oxalate

TABLE 106 absolute configuration

Example R⁴ NMR Salt 938

1H-NMR (CDCl3) δ ppm: 0.98-1.17 (23H, m), 1.17-1.40 (6H, m), 1.43 (3H,s), 1.59-1.68 (1H, m), 1.68-1.80 (3H, m) 2.32-2.41 (1H, m), 2.68 (1H, d,J = 11.3 Hz), 2.77-2.85 (1H, m), 2.88 (1H, d, J = 11.3 Hz), 7.08 (1H,dd, J = 2.4, 8.8 Hz), 7.16 (1H, d, J = 2.4 Hz), 7.22 (1H, dd, J = 2.1,8.7 Hz), 7.37 (1H, d, J = 1.8 Hz), 7.57-7.64 (2H, m). — 939

1H-NMR (CDCl3) δ ppm: 0.82-1.18 (23H, m), 1.20-1.40 (6H, m), 1.43 (3H,s), 1.59-1.70 (1H, m), 1.70-1.85 (3H, m), 2.35-2.45 (1H, m), 2.69 (1H,d, J = 11.3 Hz), 2.77-2.86 (1H, m), 2.91 (1H, d, J = 11.3 Hz), 7.02 (1H,dd, J = 2.4, 8.8 Hz), 7.09-7.15 (2H, m), 7.27 (1H, d, J = 1.9 Hz),7.61-7.68 (2H, m). — 940

1H-NMR (CDCl3) δ ppm: 0.97-1.41 (29H, m), 1.43 (3H, s), 1.59-1.70 (1H,m), 1.70-1.80 (3H, m), 2.34-2.44 (1H, m), 2.69 (1H, d, J = 11.3 Hz),2.78-2.87 (1H, m), 2.89 (1H, d, J = 11.3 Hz), 7.11 (1H, d, J = 8.9 Hz),7.34 (1H, dd, J = 2.1, 9.0 Hz), 7.37 (1H, d, J = 1.9 Hz), 7.53 (1H, d, J= 8.9 Hz), 8.10 (1H, d, J = 8.9 Hz). — 941

1H-NMR (CDCl3) δ ppm: 0.75-1.42 (29H, m), 1.44 (3H, s), 1.58-1.83 (4H,m), 2.34-2.42 (1H, m), 2.68 (1H, d, J = 11.3 Hz), 2.78-2.87 (1H, m),2.91 (1H, d, J = 11.3 Hz), 3.91 (3H, s), 5.19-5.27 (2H, m), 7.21 (1H, d,J = 9.1 Hz), 7.29 (1H, d, J = 2.2, 9.1 Hz), 7.37 (1H, d, J = 2.1 Hz),7.69 (1H, d, J = 9.0 Hz), 8.16 (1H, d, J = 9.1 Hz). — 942

1H-NMR (CDCl3) δ ppm: 0.95-1.18 (23H, m), 1.18-1.40 (6H, m), 1.44 (3H,s), 1.57-1.77 (4H, m), 2.33-2.41 (1H, m), 2.71 (1H, d, J = 11.2 Hz),2.77-2.85 (1H, m), 2.87 (1H, d, J = 11.2 Hz), 3.89 (3H, s), 4.94 (2H, d,J = 1.0 Hz), 7.02 (1H, s), 7.22 (1H, dd, J = 2.0, 8.6 Hz), 7.43 (1H, d,J = 1.8 Hz), 7.84 (1H, d, J = 8.6 Hz), 7.88 (1H, s). —

TABLE 107 absolute configuration

Example R⁴ NMR Salt 943

1H-NMR (DMSO-d6) δ ppm: 0.88-1.03 (4H, m), 1.10-1.37 (6H, m), 1.45-1.68(5H, m), 2.25-2.36 (1H, m), 2.58 (1H, d, J = 10.9 Hz), 2.62-2.71 (1H,m), 2.73 (1H, d, J = 10.9 Hz), 7.02 (1H, dd, J = 2.4, 8.7 Hz), 7.05 (1H,d, J = 2.4 Hz), 7.16 (1H, dd, J = 2.1, 8.7 Hz), 7.37 (1H, d, J = 1.8Hz), 7.58 (1H, d, J = 8.8 Hz), 7.67 (1H, d, J = 8.8 Hz), 9.57 (1H, brs).— 944

1H-NMR (DMSO-d6) δ ppm: 0.88-1.04 (4H, m), 1.12-1.37 (8H, m), 1.45-1.74(5H, m), 2.32-2.41 (1H, m), 2.60 (1H, d, J = 11.1 Hz), 2.63-2.72 (1H,m), 2.80 (1H, d, J = 11.1 Hz), 6.94 (1H, dd, J = 2.4, 8.8 Hz), 6.97-7.04(2H, m), 7.21 (1H, d, J = 1.8 Hz), 7.64 (2H, d, J = 8.8 Hz), 9.62 (1H,s). — 945

1H-NMR (DMSO-d6) δ ppm: 0.90-1.10 (4H, m), 1.15-1.40 (6H, m), 1.51-1.75(4H, m), 2.35-2.48 (1H, m), 2.60-2.88 (3H, m), 2.96- 3.88 (1H, br), 7.23(1H, d, J = 8.9 Hz), 7.34 (1H, dd, J = 2.1, 9.0 Hz), 7.47 (1H, d, J =2.0 Hz), 7.70 (1H, d, J = 8.9 Hz), 7.92 (1H, d, J = 9.0 Hz), 8.92-11.38(1H, br). — 946

1H-NMR (DMSO-d6) δ ppm: 0.93-1.12 (4H, m), 1.15-1.41 (6H, m), 1.54-1.80(4H, m), 2.48-2.60 (1H, m), 2.70-2.87 (2H, m), 2.92 (1H, d, J = 11.5Hz), 3.03-4.36 (1H, br), 7.08- 7.18 (2H, m), 7.50 (1H, d, J = 2.0 Hz),7.67 (1H, d, J = 8.8 Hz), 7.75 (1H, d, J = 8.7 Hz), 8.89-11.11 (1H, br).— 947

1H-NMR (DMSO-d6) δ ppm; 0.90-1.05 (4H, m), 1.13-1.37 (6H, m), 1.47-1.70(5H, m), 2.30-2.39 (1H, m), 2.61 (1H, d, J = 11.0 Hz), 2.64-2.73 (1H,m), 2.78 (1H, d, J = 11.0 Hz) 3.88 (3H, s), 4.81 (1H, t, J = 5.2 Hz),4.88 (2H, d, J = 5.2 Hz), 7.27 (1H, dd, J = 2.2, 9.1 Hz), 7.35 (1H, d, J= 9.1 Hz), 7.42 (1H, d, J = 2.1 Hz), 7.80 (1H, d, J = 9.1 Hz), 8.03 (1H,d, J = 9.1 Hz). — 948

1H-NMR (DMSO-d6) δ ppm: 0.95-1.10 (1H, m), 1.10-1.50 (9H, m), 1.53-1.73(3H, m), 1.77-1.87 (1H, m), 2.58-2.70 (1H, m), 2.85 (2H, s), 2.89-3.00(1H, m), 3.87 (3H, s), 4.61 (2H, s), 6.46 (1H, s), 7.20 (1H, dd, J =2.0, 8.7 Hz), 7.22 (1H, s), 7.46 (1H, d, J = 1.6 Hz), 7.73 (1H, d, J =8.7 Hz), 7.79 (1H, s). ½ Fumarate

TABLE 108 absolute configuration

Example R⁴ NMR Salt 949

1H-NMR (CDCl3) δ ppm: 0.91-1.05 (1H, m), 1.08 (3H, s), 1.12-1.62 (9H,m), 1.68-1.78 (2H, m), 2.42-2.50 (1H, m), 2.62 (1H, d, J = 11.3 Hz),2.75 (1H, d, J = 11.3 Hz), 2.91-3.00 (1H, m), 3.98 (3H, s), 6.78 (1H, d,J = 8.1 Hz), 7.20 (1H, d, J = 8.1 Hz), 7.43-7.54 (2H, m), 8.21-8.26 (1H,m), 8.50-8.54 (1H, m). — 950

1H-NMR (DMSO-d6) δ ppm: 0.93-1.22 (2H, m), 1.26-1.44 (5H, m), 1.44-1.54(1H, m), 1.56-1.77 (5H, m), 1.00-2.08 (1H, m), 2.62 (3H, s), 2.76 (1H,d, J = 12.4 Hz), 2.98-3.08 (2H, m), 3.33-3.50 (1H, m), 7.28 (1H, d, J =7.5 Hz), 7.38 (1H, d, J = 7.5 Hz), 7.54-7.61 (2H, m), 7.97-8.03 (1H, m),8.43-8.52 (1H, m), 9.10-9.25 (1H, br), 9.62-9.77 (1H, br). Hydrochloride951

1H-NMR (DMSO-d6) δ ppm: 1.00-1.30 (2H, m), 1.30-1.45 (4H, m), 1.45-1.65(2H, m), 1.65-1.85 (5H, m), 2.00-2.13 (1H, m), 2.91 (1H, d, J = 12.6Hz), 3.05-3.20 (2H, m), 3.41- 3.57 (1H, m), 3.93-4.29 (1H, br),7.61-7.77 (5H, m), 7.98-8.05 (1H, m), 8.55-8.61 (1H, m), 8.77-8.88 (2H,m), 9.19-9.35 (1H, m), 9.669.81 (1H, m). 2 Hydrochloride 952

1H-NMR (DMSO-d6) δ ppm: 0.96-1.45 (6H, m), 1.55-1.80 (7H, m), 2.00-2.12(1H, m), 2.85-3.40 (4H, m), 3.87 (3H, s), 7.05-7.26 (2H, m), 7.32 (1H,d, J = 2.5 Hz), 7.42-7.73 (1H, br), 7.73-7.90 (2H, m), 8.75-9.60 (2H,br), 9.60-10.15 (1H, br). 2 Hydrochloride 953

1H-NMR (DMSO-d6) δ ppm: 0.85-1.00 (1H, m), 1.10-1.70 (12H, m), 1.75-1.87(1H, m), 2.62-2.81 (3H, m), 2.98-3.12 (1H, m), 3.20- 3.45 (4H, m), 6.46(1H, s), 7.15-7.35 (3H, m), 7.35-7.52 (1H, m), 7.88 (1H, d, J = 8.1 Hz),8.05-9.35 (1H, br). ½ Fumarate 954

1H-NMR (DMSO-d6) δ ppm: 1.05-1.45 (6H, m), 1.55-1.80 (7H, m), 1.90-2.10(1H, m), 2.91-3.08 (2H, m), 3.08-3.30 (2H, m), 3.98 (3H, s), 7.44 (1H,d, J = 8.0 Hz), 7.56 (1H, d, J = 9.2 Hz), 7.67 (1H, brs), 7.96 (1H, d, J= 9.1 Hz), 8.05 (1H, d, J = 9.1 Hz), 8.15-9.10 (1H, br), 9.17-9.40 (1H,m), 9.69-9.89 (1H, m). 2 Hydrochloride 955

1H-NMR (CDCl3) δ ppm: 0.60-0.98 (1H, br), 1.03-1.17 (4H, m), 1.22-1.47(6H, m), 1.63- 1.74 (1H, m), 1.74-1.89 (3H, m), 2.45-2.55 (1H, m), 2.76(1H, d, J = 11.5 Hz), 2.81-2.90 (1H, m), 2.98 (1H, d, J = 11.5 Hz),7.38-7.44 (2H, m), 7.49 (1H, dd, J = 1.6, 8.4 Hz), 7.76- 7.81 (1H, m),7.83 (1H, d, J = 8.4 Hz), 8.12 (1H, s). — 956

1H-NMR (DMSO-d6) δ ppm: 1.12-1.45 (6H, m), 1.55-1.90 (7H, m), 2.00-2.14(1H, m), 3.08-3.40 (4H, m), 4.52-5.08 (1H, br), 7.46 (1H, dd, J = 2.0,8.9 Hz), 7.64 (1H, d, J = 1.7 Hz), 7.73 (1H, dd, J = 1.6, 8.5 Hz), 8.00(1H, d, J = 8.9 Hz), 8.04 (1H, d, J = 8.6 Hz), 8.49 (1H, s), 9.10-9.25(1H, br), 9.60-9.75 (1H, br). 2 Hydrochloride 957

1H-NMR (DMSO-d6) δ ppm: 1.03-1.45 (6H, m), 1.50-1.80 (7H, m), 1.98-2.10(1H, m), 2.90-3.30 (4H, m), 3.95 (3H, s), 6.91 (1H, d, J = 7.1 Hz),7.23-7.34 (1H, br), 7.38-7.49 (2H, m), 7.48-7.65 (1H, br), 8.10 (1H, d,J = 8.9 Hz), 9.10-9.36 (1H, br), 9.60-9.88 (1H, br), 10.00-11.50 (1H,br). 2 Hydrochloride 958

1H-NMR (DMSO-d6) δ ppm: 1.10-1.48 (6H, m), 1.55-1.80 (7H, m), 1.981-2.10(1H, m), 2.95-3.10 (2H, m), 3.10-3.21 (1H, m), 3.21- 3.85 (1H, m), 3.99(3H, s), 7.26 (1H, dd, J = 1.5, 8.7 Hz), 7.50 (1H, d, J = 9.1 Hz), 7.66(1H, brs), 7.93 (2H, d, J = 9.1 Hz), 9.20 (1H, brs), 9.72 (1H, brs),9.89-10.70 (1H, brs). 2 Hydrochloride 959

1H-NMR (DMSO-d6) δ ppm: 1.10-1.43 (6H, m), 1.56-1.80 (7H, m), 1.99-2.00(1H, m), 2.95-3.06 (2H, m), 3.11 (1H, d, J = 12.5 Hz), 3.17-3.30 (1H,m), 6.05-7.25 (1H, br), 7.36 (1H, dd, J = 1.9, 8.0 Hz), 7.49 (1H, dd, J= 2.1, 8.8 Hz), 7.64 (1H, brs), 7.88 (1H, d, J = 3.9 Hz), 7.94 (1H, d, J= 8.9 Hz), 8.00 (1H, d, J = 1.8 Hz), 9.15-9.34 (1H, br), 9.69-9.85 (1H,br). 2 Hydrochloride 960

1H-NMR (CDCl3) δ ppm: 0.75-1.19 (5H, m), 1.24-1.44 (3H, m), 1.41 (3H,s), 1.59-1.73 (1H, m), 1.73-1.82 (2H, m), 1.90-2.00 (1H, m), 2.45-2.54(1H, m), 2.73 (1H, d, J = 11.5 Hz), 2.81-2.92 (1H, m), 3.02 (1H, d, J =11.5 Hz), 7.26 (1H, dd, J = 2.1, 9.0 Hz), 7.38-7.47 (2H, m), 7.51 (1H,d, J = 1.3 Hz), 7.91 (1H, d, J = 9.1 Hz), 7.94-7.99 (2H, m), 8.30 (1H,s), 8.34 (1H, s). — 961

1H-NMR (DMSO-d6) δ ppm: 1.15-1.48 (6H, m), 1.55-1.80 (7H, m), 1.95-2.09(1H, m), 2.91-3.05 (2H, m), 3.05-3.16 (1H, m), 3.16- 3.30 (1H, m),3.70-4.4.10 (1H, br), 7.16 (0.25H, s), 7.32-7.40 (2.5H, m), 7.53 (0.25H,s), 7.62-7.70 (2H, m), 7.90 (1H, d, J = 8.8 Hz), 7.98 (1H, d, J = 9.0Hz), 9.05-9.25 (1H, br), 9.54-9.78 (1H, br). 2 Hydrochloride 962

1H-NMR (DMSO-d6) δ ppm: 1.05-1.50 (6H, m), 1.55-1.60 (7H, m), 1.97-2.10(1H, m), 2.40-3.05 (2H, m), 3.05-3.16 (1H, m), 3.16- 3.31 (1H, m),3.65-4.25 (4H, m), 7.44 (1H, dd, J = 2.0, 8.8 Hz), 7.56 (1H, s), 7.65(1H, s), 7.89 (1H, d, J = 8.8 Hz), 8.47 (1H, s), 9.05- 9.35 (1H, br),9.53-9.84 (1H, br). 2 Hydrochloride 963

1H-NMR (DMSO-d6) δ ppm: 1.08-1.46 (6H, m), 1.54-1.80 (7H, m), 1.97-2.08(1H, m), 2.95-3.17 (3H, m), 3.17-3.31 (1H, m) 4.65- 4.45 (1H, br),7.46-7.50 (1H, m), 7.57-7.67 (3H, m), 7.97-8.04 (1H, m), 8.07-8.15 (1H,m), 9.13-9.35 (1H, br), 9.62-9.80 (1H, br). 2 Hydrochloride 964

1H-NMR (DMSO-d6) δ ppm: 1.08-1.47 (6H, m), 1.53-1.82 (7H, m), 1.98-2.09(1H, m), 2.93-3.17 (3H, m), 3.17-3.30 (1H, m), 4.30- 4.85 (1H, br), 7.15(1H, dd, J = 1.6, 12.4 Hz), 7.47 (1H, d, J = 1.3 Hz), 7.51-7.64 (2H, m),7.97 (2H, d, J = 8.2 Hz), 9.10-9.30 (1H, br), 9.67-9.85 (1H, br). 2Hydrochloride 965

1H-NMR (CDCl3) δ ppm: 1.00-1.15 (4H, m), 1.17-1.52 (7H, m), 1.58-1.68(1H, m), 1.68- 1.79 (3H, m), 2.34-2.42 (1H, m), 2.69 (1H, d, J = 11.3Hz), 2.77-2.86 (1H, m), 2.88 (1H, d, J = 11.3 Hz), 4.28 (2H, dt, J =4.1, 13.1 Hz), 6.15 (1H, tt, J = 4.1, 55.2 Hz), 7.10 (1H, d, J = 2.5Hz), 7.14 (1H, dd, J = 2.6, 8.9 Hz), 7.27 (1H, dd, J = 2.1. 8.7 Hz),7.41 (1H, d, J = 2.0 Hz), 7.63-7.72 (2H, m). — 966

1H-NMR (CDCl3) δ ppm: 1.00-1.15 (4H, m), 1.20-1.70 (8H, m), 1.70-1.88(3H, m), 2.39- 2.48 (1H, m), 2.70 (1H, d, J = 11.4 Hz), 2.79- 2.88 (1H,m), 2.93 (1H, d, J = 11.4 Hz), 4.29 (2H, dt, J = 4.2, 13.1 Hz), 6.15(1H, tt, J = 4.1, 55.2 Hz), 7.03-7.11 (2H, m), 7.16 (1H, dd, J = 2.1,8.6 Hz), 7.33 (1H, d, J = 2.0 Hz), 7.65- 7.74 (2H, m). — 967

1H-NMR (DMSO-d6) δ ppm: 0.91-1.05 (1H, m), 1.07-1.36 (5H, m), 1.36-1.63(12H, m), 1.63-1.74 (1H, m), 1.80-1.83 (1H, m) 2.50- 2.62 (1H, m), 2.71(1H, d, J = 12.0 Hz), 2.86 (1H, d, J = 12.0 Hz), 2.92-3.02 (1H, m), 4.78(2H, s), 6.48 (2H, s), 6.73 (1H, d, J = 8.6 Hz), 6.83 (1H, d, J = 2.3Hz), 6.91 (1H, dd, J = 2.3, 8.6 Hz), 9.52-11.33 (1H, br). Fumarate

TABLE 109 absolute configuration

Example R⁴ NMR Salt 968

1H-NMR (DMSO-d6) δ ppm: 0.96-1.10 (1H, m), 1.10-1.25 (1H, m), 1.25-1.41(4H, m), 1.47-1.78 (7H, m), 1.94-2.05 (1H, m), 2.56 (3H, s), 2.84 (1H,d, J = 12.4 Hz), 2.90-3.02 (2H, m), 3.23-3.35 (1H, m), 7.15 (1H, d, J =7.6 Hz), 7.22-7.33 (2H, m), 7.68 (1H, d, J = 7.9 Hz), 8.91-9.09 (1H,brm), 9.54-9.70 (1H, brm). Hydrochloride 969

1H-NMR (DMSO-d6) δ ppm (80° C): 1.03- 1.46 (6H, m), 1.50-1.79 (7H, m),2.02-2.12 (1H, m), 2.53 (3H, s), 2.88 (1H, d, J = 12.4 Hz), 3.02-3.12(1H, m), 3.12-3.27 (2H, m), 7.05 (1H, s), 7.13 (1H, d, J = 8.6 Hz),7.62- 7.68 (2H, m), 9.25 (1H, brs), 9.75 (1H, brs). Hydrochloride 970

1H-NMR (DMSO-d6) δ ppm: 0.95-1.41 (6H, m), 1.40-1.76 (7H, m), 1.96-2.05(1H, m), 2.84 (1H, d, J = 12.4 Hz), 2.93-3.01 (1H, m), 3.04 (1H, d, J =12.4 Hz), 3.28-3.44 (1H, m), 7.25 (2H, d, J = 7.0 Hz), 7.64 (1H, dd, J =4.0, 5.3 Hz), 7.86 (1H, d, J = 5.3 Hz), 9.04-9.19 (1H, brm), 9.63-9.75(1H, brm). Hydrochloride 971

1H-NMR (DMSO-d6) δ ppm: 0.97-1.43 (6H, m), 1.45-1.78 (7H, m), 1.96-2.06(1H, m), 2.87 (1H, d, J = 12.4 Hz), 2.94-3.06 (2H, m), 3.26- 3.43 (1H,m), 7.28 (1H, d, J = 8.1 Hz), 7.50 (1H, d, J = 8.1 Hz), 7.64 (1H, d, J =5.4 Hz), 7.88 (1H, d, J = 5.4 Hz), 9.12 (1H, brs), 9.66 (1H, brs).Hydrochloride 972

1H-NMR (DMSO-d6) δ ppm: 0.92-1.80 (13H, m), 1.36-2.05 (1H, m), 2.75-3.05(4H, m), 3.94 (3H, s), 6.94 (1H, d, J = 7.9 Hz), 7.18 (1H, d, J = 7.9Hz), 7.55 (1H, d, J = 5.4 Hz), 7.71 (1H, d, J = 5.4 Hz), 8.81 (1H, brs),9.31 (1H, brs). Hydrochloride 973

1H-NMR (DMSO-d6) δ ppm: 0.95-1.15 (1H, m), 1.15-1.3 (1H, m), 1.3-1.45(5H, m), 1.5- 1.7 (6H, m), 1.7, 1.8 (1H, m), 1.9-2.0 (1H m), 2.85-3.1(3H, m), 3.2-3.4 (1H, m), 7.24 (1H, d, J = 7.2 Hz), 7.42 (1H, dd, J =7.7, 7.7 Hz), 7.70-7.77 (2H, m), 8.84 (1H, br), 9.28 (1H, br).Hydrochloride

TABLE 110 absolute configuration

Example R⁴ NMR Salt 974

1H-NMR (DMSO-d6) δ ppm: 0.97-1.10 (1H, m), 1.10-1.41 (5H, m), 1.50-1.78(7H, m), 1.94-2.05 (1H, m), 2.44 (3H, s), 2.75-3.09 (3H, m), 3.09-3.30(1H, m), 6.58 (1H, brs), 6.98 (1H, d, J = 7.2 Hz), 7.19 (1H, t, J = 7.8Hz), 7.31 (1H, d, J = 7.8 Hz), 9.00 (1H, brs), 9.59 (1H, brs).Hydrochloride 975

1H-NMR (DMSO-d6) δ ppm: 1.00-1.44 (6H, m), 1.44-1.79 (7H, m), 1.95-2.08(1H, m), 2.42 (3H, d, J = 0.9 Hz), 2.78-3.30 (4H, m), 3.78- 4.64 (1H,br), 6.55 (1H, s), 7.04 (1H, brs), 7.32 (1H, brs), 7.48 (1H, d, J = 8.6Hz), 8.91- 9.35 (1H, br), 9.54-9.90 (1H, br). 2 Hydrochloride 976

1H-NMR (DMSO-d6) δ ppm: 1.00-1.14 (1H, m), 1.14-1.42 (5H, m), 1.43-1.77(7H, m), 1.93-2.03 (1H, m), 2.72-3.12 (3H, m), 3.27 (1H, brs), 7.08 (1H,brs), 7.24 (1H, brs), 8.14 (1H, s), 8.95 (1H, brs), 9.57 (1H, brs).Hydrochloride 977

1H-NMR (CDCl3) δ ppm: 0.86-1.13 (5H, m), 1.13-1.40 (3H, m), 1.42 (3H,s), 1.57-1.68 (2H, m), 1.68-1.79 (2H, m), 2.20-2.30 (1H, m), 2.65 (1H,d, J = 11.1 Hz), 2.74-2.85 (2H, m), 3.99 (3H, s), 6.61 (1H, d, J = 1.8Hz), 6.70 (1H, d, J = 2.1 Hz), 6.95 (1H, d, J = 1.8 Hz), 7.59 (1H, d, J= 2.1 Hz). — 978

1H-NMR (DMSO-d6) δ ppm: 1.02-1.42 (6H, m), 1.49-1.78 (7H, m), 1.96-2.06(1H, m), 2.82-2.97 (2H, m), 3.04-3.25 (2H, m), 6.55- 7.25 (3H, m), 7.30(1H, s), 8.11 (1H, d, J = 2.1 Hz), 9.11-9.30 (1H, m), 9.70-9.86 (1H, m).2 Hydrochloride 979

1H-NMR (DMSO-d6) δ ppm: 1.00-1.40 (6H, m), 1.45-1.78 (7H, m), 1.95-2.05(1H, m), 2.82-2.95 (2H, m), 3.02-3.24 (2H, m), 3.78- 4.47 (1H, br), 7.05(1H, d, J = 2.2 Hz), 7.19 (1H, d, J = 1.7 Hz), 7.44 (1H, d, J = 1.7 Hz),8.12 (1H, d, J = 2.2 Hz), 9.15 (1H, brs), 9.66 (1H, brs). 2Hydrochloride 980

1H-NMR (DMSO-d6) δ ppm: 0.90-1.05 (1H, m), 1.12-1.84 (13H, m), 2.55-2.95(4H, m), 3.10-4.75 (2H, br), 6.43 (3H, s), 7.34 (1H, dd, J = 2.1, 8.9Hz), 7.53 (1H, d, J = 2.0 Hz), 7.68 (1H, d, J = 8.9 Hz), 8.03 (1H, d, J= 0.8 Hz). Fumarate 981

1H-NMR (CDCl3) δ ppm: 0.96-1.15 (4H, m), 1.15-1.45 (6H, m), 1.48-1.80(5H, m), 2.21- 2.30 (1H, m), 2.62 (1H, d, J = 11.1 Hz), 2.75- 2.85 (2H,m), 7.04 (1H, dd, J = 1.8, 11.8 Hz), 7.15 (1H, d, J = 1.8 Hz), 7.42 (1H,d, J = 2.5 Hz). — 982

1H-NMR (CDCl3) δ ppm: 0.96-1.15 (4H, m), 1.15-1.40 (3H, m), 1.42 (3H,s), 1.55-1.70 (3H, m), 1.70-1.80 (2H, m), 2.23-2.35 (1H, m), 2.66 (1H,d, J = 11.1 Hz), 2.75-2.86 (2H, m), 4.01 (3H, s), 6.76 (1H, d, J = 1.7Hz), 6.97 (1H, d, J = 1.7 Hz), 7.38 (1H, s). — 983

1H-NMR (DMSO-d6) δ ppm: 0.99-1.42 (6H, m), 1.50-1.78 (7H, m), 1.72-2.05(1H, m), 2.75-3.11 (3H, m), 3.16-3.40 (1H, br), 4.95- 6.80 (1H, br),6.95-7.11 (2H, m), 7.12-7.21 (1.25H, m), 7.33 (0.5H, s), 7.51 (0.25H,s), 8.08 (1H, brs), 9.05 (1H, brs), 9.64 (1H, brs). 2 Hydrochloride 984

1H-NMR (CDC13) δ ppm: 0.99-1.12 (4H, m), 1.20-1.43 (7H, m), 1.62-1.83(4H, m), 2.34- 2.42 (1H, m), 2.70 (1H, d, J = 11.5 Hz), 2.76- 2.85 (1H,m), 2.91 (1H, d, J = 11.5 Hz), 3.92 (3H, s), 6.45 (1H, d, J = 1.4 Hz),6.80-6.83 (1H, m), 7.45 (1H, d, J = 0.9 Hz). — 985

1H-NMR (CDCl3) δ ppm: 1.01-1.15 (4H, m), 1.20-1.45 (7H, m), 1.67-1.90(4H, m), 2.44- 2.53 (1H, m), 2.77-2.87 (2H, m), 2.98 (1H, d, J = 11.9Hz), 6.74 (1H, dd, J = 1.6, 11.5 Hz), 6.90-6.94 (1H, m), 7.43 (1H, d, J= 0.9 Hz). —

TABLE 111 absolute configuration

Example R⁴ NMR Salt 986

1H-NMR (CDCl3) δ ppm: 0.83-1.44 (26H, m), 1.52 (3H, s), 1.55-1.90 (7H,m), 2.36-2.62 (2H, m), 2.80-3.00 (2H, m), 6.69-6.84 (3H, m), 7.24 (1H,d, J = 3.2 Hz). — 987

1H-NMR (CDCl3) δ ppm: 0.80-1.38 (26H, m), 1.42 (3H, s), 1.58-1.77 (4H,m), 2.01 (3H, sextet, J = 7.5 Hz), 2.25-2.34 (1H, m), 2.65 (1H, d, J =11.2 Hz.), 2.75-2.85 (2H, m), 7.11 (1H, dd, J = 2.1, 9.1 Hz), 7.32 (1H,d, J = 2.1 Hz), 7.33 (1H, d, J = 0.5 Hz), 7.50 (1H, d, J = 9.1 Hz). —988

1H-NMR (CDCl3) δ ppm: 0.76-1.40 (26H, m), 1.52 (3H, s), 1.56-1.94 (7H,m), 2.35-2.64 (2H, m), 2.79-3.01 (2H, m), 3.88 (3H, s), 6.54 (1H, d, J =8.1 Hz), 6.69 (1H, d, J = 3.1 Hz), 6.74 (1H, d, J = 8.1 Hz), 7.24 (1H,d, J = 3.2 Hz). — 989

1H-NMR (CDCl3) δ ppm: 0.95-1.20 (22H, m), 1.20-1.45 (3H, m), 1.52 (3H,s), 1.62-1.90 (7H, m), 2.10-2.20 (1H, m), 2.57-2.68 (2H, m), 2.83-2.95(1H, m), 3.26 (1H, d, J = 11.7 Hz), 6.55 (1H, d, J = 3.5 Hz), 6.63 (1H,d, J = 5.2 Hz), 7.18 (1H, d, J = 3.5 Hz), 8.12 (1H, d, J = 5.2 Hz). —990

1H-NMR (CDCl3) δ ppm: 0.96-1.17 (23H, m), 1.17-1.40 (3H, m), 1.42 (3H,s), 1.55-1.66 (2H, m), 1.66-1.76 (2H, m), 1.84 (3H, quint, J = 7.5 Hz),2.28-2.37 (1H, m), 2.72 (1H, d, J = 11.2 Hz), 2.76-2.85 (2H, m), 6.47(1H, d, J = 3.4 Hz), 7.27 (1H, d, J = 3.4 Hz), 7.61 (1H, d, J = 2.4 Hz),8.06 (1H, d, J = 2.4 Hz). — 991

1H-NMR (CDCl3) δ ppm: 0.89-1.40 (26H, m), 1.43 (3H, s), 1.60-1.80 (4H,m), 1.95-2.07 (3H, m), 2.30-2.40 (1H, m), 2.58 (1H, d, J = 11.3 Hz),2.80-2.90 (2H, m), 6.98 (1H, d, J = 1.6, 8.5 Hz), 7.31 (1H, s), 7.34(1H, d, J = 0.6 Hz), 7.52 (1H, d, J = 8.5 Hz). —

TABLE 112 absolute configuration

Example R⁴ NMR Salt 992

1H-NMR (DMSO-d6) δ ppm: 0.77-0.92 (1H, m), 0.95 (3H, s), 1.09-1.35 (3H,m), 1.40 (3H, s), 1.46-1.57 (2H, m), 1.58-1.83 (3H, m), 2.29- 2.47 (2H,m), 2.60-2.85 (2H, m), 6.47 (1H, brs), 6.58-6.65 (1H, m), 6.81 (1H, dd,J = 8.3, 11.0 Hz), 7.30 (1H, t, J = 2.7 Hz), 11.47 (1H, s). — 993

1H-NMR (DMSO-d6) δ ppm: 0.83-1.00 (4H, m), 1.08-1.34 (6H, m), 1.41-1.67(5H, m), 2.19-2.27 (1H, m), 2.55 (1H, d, J = 10.8 Hz), 2.59-2.69 (2H,m), 7.11 (1H, dd, J = 1.8, 8.8 Hz), 7.26 (1H, d, J = 0.8 Hz), 7.32 (1H,d, J = 1.8 Hz), 7.32 (1H, d, J = 8.8 Hz), 12.25 (1H, brs). — 994

1H-NMR (CDCl3) δ ppm: 0.75-0.99 (4H, m), 1.08-1.90 (11H, m), 2.20-2.45(2H, m), 2.58- 2.86 (2H, m), 3.86 (3H, s), 6.38 (1H, brs), 6.47-6.66(2H, m), 7.13 (1H, t, J = 2.5 Hz), 11.07 (1H, s). — 995

1H-NMR (DMSO-d6) δ ppm: 0.95-1.09 (1H, m), 1.21 (3H, s), 1.25-1.65 (7H,m), 1.69-1.79 (1H, m), 1.86-2.03 (2H, m), 2.88 (1H, d, J = 12.4 Hz),2.96-3.21 (3H, m), 6.39 (1H, d, J = 2.6 Hz), 6.49 (2H, s), 6.72 (1H, d,J = 5.3 Hz), 7.33-7.38 (1H, m), 8.09 (1H, d, J = 5.3 Hz), 8.35-11.15(1H, br), 11.58 (1H, s). Fumarate 996

1H-NMR (DMSO-d6) δ ppm: 0.95-1.10 (1H, m), 1.10-1.23 (1H, m), 1.23-1.38(4H, m), 1.38-1.60 (6H, m), 1.63-1.75 (1H, m), 1.84- 1.95 (1H, m),2.72-2.85 (2H, m), 3.00-3.13 (2H, m), 6.38-6.43 (1H, m), 6.50 (1H, s),7.43- 7.48 (1H, m), 7.75 (1H, d, J = 1.9 Hz), 7.99 (1H, d, J = 2.2 Hz),8.35-11.30 (2H, br), 11.61 (1H, s). ½ Fumarate 997

1H-NMR (DMSO-d6) δ ppm: 0.85-1.05 (4H, m), 1.10-1.36 (6H, m), 1.35-2.10(5H, m), 2.25-2.35 (1H, m), 2.56 (1H, d, J = 11.0 Hz), 2.62-2.70 (1H,m), 2.75 (1H, d, J = 11.0 Hz), 6.91 (1H, dd, J = 1.2, 8.6 Hz), 7.02 (1H,s), 7.27 (1H, s), 7.55 (1H, d, J = 8.6 Hz) 11.93- 12.33 (1H, br). —

TABLE 113 absolute configuration

Example R⁴ NMR Salt 998

1H-NMR (CDCl3) δ ppm: 0.72-1.19 (5H, m), 1.25-1.45 (3H, m), 1.48 (3H,s), 1.65-1.82 (3H, m), 2.08-2.20 (1H, m), 2.65-2.80 (2H, m), 2.80- 2.95(1H, m), 3.27 (1H, d, J = 11.9 Hz), 3.85 (3H, s), 6.45 (1H, d, J = 3.5Hz), 6.63 (1H, d, J = 5.3 Hz), 7.06 (1H, d, J = 3.5 Hz), 8.20 (1H, d, J= 5.3 Hz). — 999

1H-NMR (DMSO-d6) δ ppm: 0.95-1.60 (11H, m), 1.60-1.83 (2H, m), 1.83-1.95(1H, m), 2.65- 2.83 (2H, m), 3.00-3.10 (2H, m), 3.79 (3H, s), 6.41 (1H,d, J = 3.4 Hz), 6.48 (2H, s), 7.50 (1H, d, J = 3.4 Hz), 7.77 (1H, d, J =2.2 Hz), 8.04 (1H, d, J = 2.2 Hz), 8.35-10.85 (2H, br). Fumarate

TABLE 114 absolute configuration

Example R⁴ NMR Salt 1000

1H-NMR (DMSO-d6) δ ppm: 0.87-1.00 (1H, m), 1.15-1.40 (5H, m), 1.50-1.78(7H, m), 1.90- 2.11 (3H, m), 2.65-2.80 (2H, m), 2.80-3.05 (5H, m),3.09-3.25 (1H, m), 3.48 (1H, brs), 6.99 (1H, d, J = 8.3 Hz), 7.21 (1H,d, J = 8.3 Hz), 8.90- 9.10 (1H, m), 9.40-9.64 (1H, m). 2 Hydrochloride1001

1H-NMR (DMSO-d6) δ ppm: 0.89-1.04 (1H, m), 1.20-1.40 (5H, m), 1.46-1.78(7H, m), 1.88- 2.09 (3H, m), 2.64-3.00 (7H, m), 3.05-3.25 (1H, m),3.25-3.50 (1H, br), 6.96 (1H, s), 7.12 (1H, s), 8.70-9.10 (1H, brs),9.15-9.55 (1H, brs). 2 Hydrochloride 1002

1H-NMR (DMSO-d6) δ ppm: 0.90-1.21 (2H, m), 1.22-1.43 (4H, m), 1.43-1.80(7H, m), 1.90- 2.10 (1H, m), 2.58-3.40 (6H, m), 4.52 (2H, t, J = 8.6Hz), 5.35-6.40 (1H, br), 6.55-7.60 (3H, m), 8.60-10.20 (2H, br). 2Hydrochloride 1003

1H-NMR (DMSO-d6) δ ppm: 0.98-1.13 (1H, m), 1.13-1.40 (5H, m), 1.47-1.65(6H, m), 1.65- 1.77 (1H, m), 1.91-2.06 (1H, m), 2.74-2.90 (2H, m), 2.99(1H, d, J = 12.5 Hz), 3.08-3.21 (1H, m), 4.05-5.00 (1H, br), 6.95 (1H,dd, J = 2.0, 8.6 Hz), 7.26 (1H, d, J = 2.0 Hz), 7.36 (1H, d, J = 8.6Hz), 8.94-9.20 (1H, br), 9.55-9.85 (1H, br). 2 Hydrochloride

TABLE 115 absolute configuration

Example R⁴ NMR Salt 1004

1H-NMR (CDCl3) δ ppm: 0.78-1.04 (2H, m), 1.04-1.14 (21H, m), 1.15-1.35(6H, m), 1.38 (3H, s), 1.51-1.75 (4H, m), 2.12-2.20 (1H, m), 2.58 (1H,d, J = 11.1 Hz), 2.69-2.78 (2H, m), 6.76-6.81 (2H, m), 6.92-6.97 (2H,m). — 1005

1H-NMR (CDCl3) δ ppm: 0.85-1.15 (23H, m), 1.15-1.37 (6H, m), 1.38 (3H,s), 1.60-1.77 (4H, m), 2.20-2.29 (1H, m), 2.58 (1H, d, J = 11.3 Hz),2.72-2.82 (2H, m), 6.60-6.65 (2H, m), 6.65-6.70 (1H, m), 7.07-7.13 (1H,m). — 1006

1H-NMR (CDCl3) δ ppm: 0.75-1.13 (23H, m), 1.13-1.39 (9H, m), 1.50-1.75(4H, m), 2.08- 2.18 (1H, m), 2.55 (1H, d, J = 11.2 Hz), 2.69- 2.78 (2H,m), 6.68-6.74 (1H, m), 6.77-6.86 (2H, m). — 1007

1H-NMR (CDCl3) δ ppm: 0.92-1.38 (29H, m), 1.39 (3H, s), 1.58-1.76 (4H,m), 2.23-2.31 (1H, m), 2.61 (1H, d, J = 11.3 Hz), 2.71-2.82 (2H, m),4.79 (2H, s), 7.02-7.08 (2H, m), 7.22-7.31 (2H, m). — 1008

1H-NMR (CDCl3) δ ppm: 0.72-1.35 (29H, m), 1.36 (3H, s), 1.60-1.78 (4H,m), 2.21-2.30 (1H, m), 2.60 (1H, d, J = 12.1 Hz), 2.71-2.84 (2H, m),5.30 (2H, s), 6.72 (1H, dd, J = 2.0, 12.0 Hz), 6.86 (1H, J = 2.0, 8.2Hz), 7.44 (1H, t, J = 8.4 Hz). — 1009

1H-NMR (CDCl3) δ ppm: 0.72-1.39 (32H, m), 1.52-1.75 (4H, m), 2.08-2.18(1H, m), 2.56 (1H, d, J = 11.1 Hz), 2.67-2.77 (2H, m), 6.80 (1H, d, J =8.6 Hz), 6.84 (1H, dd, J = 2.4, 8.6 Hz), 7.08 (1H, d, J = 2.4 Hz). —1010

1H-NMR (CDCl3) δ ppm: 0.86-1.09 (23H, m), 1.09-1.36 (3H, m), 1.37 (3H,s), 1.50-1.75 (4H, m), 2.11-2.19 (1H, m), 2.57 (1H, d, J = 11.1 Hz),2.67-2.77 (2H, m), 4.95 (2H, s), 6.67 (1H, d, J = 2.5 Hz), 6.82 (1H, d,J = 8.5 Hz), 6.91 (1H, dd, J = 2.5, 8.5 Hz). —

TABLE 116 absolute configuration

Example R⁴ NMR Salt 1011

1H-NMR (CDCl3) δ ppm: 0.92-1.06 (1H, m), 1.09 (3H, s), 1.12-1.39 (3H,m), 1.41 (3H, s), 1.55-1.66 (2H, m), 1.66-1.79 (2H, m), 2.17- 2.25 (1H,m), 2.61 (1H, d, J = 11.3 Hz), 2.70- 2.83 (2H, m), 3.53-4.70 (2H, br),6.73-6.79 (2H, m), 6.94-7.01 (2H, m). — 1012

1H-NMR (DMSO-d6) δ ppm: 0.82-1.00 (4H, m), 1.09-1.35 (6H, m), 1.40-1.52(1H, m), 1.52- 1.70 (4H, m), 2.15-2.25 (1H, m), 2.44-2.55 (1H, m),2.55-2.64 (1H, m), 2.66 (1H, d, J = 12.2 Hz), 6.39-6.51 (3H, m),6.99-7.09 (1H, m), 9.21 (1H, s). — 1013

1H-NMR (DMSO-d6) δ ppm: 0.90-1.03 (1H, m), 1.05-1.53 (10H, m), 1.53-1.62(1H, m), 1.62-1.74 (1H, m), 1.80-1.90 (1H, m), 2.48- 2.59 (1H, m), 2.68(1H, J = 11.8 Hz), 2.84 (1H, d, J = 11.8 Hz), 2.90-3.01 (1H, m), 3.74(3H, s), 4.45 (2H, s), 6.45 (1H, s), 6.86 (1H, d, J = 8.6 Hz), 6.94 (1H,dd, J = 2.5, 8.6 Hz), 7.15 (1H, d, J = 2.5 Hz), 8.10-10.15 (1H, br). ½Fumarate 1014

1H-NMR (DMSO-d6) δ ppm: 0.83-1.00 (4H, m), 1.05-1.31 (6H, m), 1.40-1.51(1H, m), 1.51- 1.65 (3H, m), 2.05-2.14 (1H, m), 2.47 (1H, d, J = 10.8Hz), 2.53-2.62 (2H, m), 3.10-3.60 (1H, br), 6.67-6.73 (1H, m), 6.79-6.87(2H, m), 9.00- 10.10 (1H, m). — 1015

1H-NMR (CDCl3) δ ppm: 0.84-1.12 (5H, m), 1.16-1.45 (6H, m), 1.59-2.14(5H, m), 2.25- 2.35 (1H, m), 2.56-2.65 (1H, m), 2.72-2.85 (2H, m), 4.64(2H, m), 7.07 (2H, dd, J = 1.3, 8.1 Hz), 7.29 (2H, d, J = 8.1 Hz). —1016

1H-NMR (CDCl3) δ ppm: 0.95-1.44 (11H, m), 1.44-2.22 (5H, m), 2.26-2.35(1H, m), 2.62 (1H, d, J = 11.4 Hz), 2.72-2.87 (2H, m), 4.69 (2H, s),6.75 (1H, dd, J = 2.0, 12.0 Hz), 6.81 (1H, dd, J = 2.0, 8.1 Hz), 7.29(1H, t, J = 8.4 Hz). — 1017

1H-NMR (CDCl3) δ ppm: 0.89-1.12 (4H, m), 1.14-1.43 (6H, m), 1.53-1.77(4H, m), 2.12- 2.21 (1H, m), 2.57 (1H, d, J = 11.2 Hz), 2.67- 2.80 (2H,m), 2.80-3.30 (2H, br), 6.89-6.96 (2H, m), 7.05-7.09 (1H, m). — 1018

1H-NMR (DMSO-d6) δ ppm: 0.78-0.94 (1H, m), 0.95 (3H, s), 1.04-1.32 (6H,m), 1.39-1.66 (5H, m), 2.05-2.15 (1H, m), 2.45-2.62 (3H, m), 4.43 (2H,s), 4.70-5.15 (1H, br), 6.65 (1H, d, J = 8.4 Hz), 6.74 (1H, dd, J = 2.5,8.4 Hz), 7.03 (1H, d, J = 2.5 Hz), 8.80-9.30 (1H, br). —

TABLE 117 absolute configuration

Example R⁵ R⁶ R⁷ R⁸ R⁹ NMR Salt 1019 —CH3 —H —H —H —H 1H-NMR (DMSO-Hydrochloride d6) δ ppm: 0.88- 1.03 (1H, m), 1.10- 1.25 (1H, m), 1.25-1.40 (4H, m), 1.45- 1.66 (6H, m), 1.67- 1.89 (1H, m), 1.92- 2.03 (1H,m), 2.26 (3H, m), 2.65 (1H, d, J = 12.5 Hz), 2.80 (1H, d, J = 12.5 Hz),2.88-3.00 (1H, m), 3.15-3.28 (1H, m), 7.06-7.17 (2H, m), 7.19-7.26 (2H,m), 9.04 (1H, brs), 9.58 (1H, brs). 1020 —CH3 —CH3 —H —H —H 1H-NMR(DMSO- Hydrochloride d6) δ ppm: 0.89- 1.02 (1H, m), 1.09- 1.23 (1H, m),1.24- 1.40 (4H, m), 1.40- 1.66 (6H, m), 1.67- 1.76 (1H, m), 1.93- 2.02(1H, m), 2.21 (3H, s), 2.22 (3H, s), 2.60 (1H, d, J = 12.5 Hz),2.76-2.95 (2H, m), 3.15-3.35 (1H, m), 6.97-7.03 (2H, m), 7.07-1.15 (1H,m), 9.07 (1H, brs), 9.61 (1H, brs). 1021 —H —F —CN —H —H 1H-NMR (DMSO-Fumarate d6) δ ppm: 1.21- 1.65 (10H, m), 1.65- 1.84 (2H, m), 1.90- 2.00(1H, m), 2.10- 2.20 (1H, m), 3.38- 3.61 (3H, m), 3.78 (1H, d, J = 14.5Hz), 6.83 (1H, dd, J = 2.3, 8.9 Hz), 6.97 (1H, dd, J = 2.0, 13.7 Hz),7.65 (1H, t, J = 8.5 Hz), 8.93- 9.15 (1H, m), 9.51- 9.71 (1H, m). 1022—H —H —OCF3 —H —H 1H-NMR (DMSO- 2 Hydrochloride d6) δ ppm: 1.00- 1.15(1H, m), 1.15- 1.40 (5H, m), 1.50- 1.67 (6H, m), 1.67- 1.77 (1H, m),1.95- 2.05 (1H, m), 2.80- 2.95 (2H, m), 3.01 (1H, d, J = 12.4 Hz),3.11-3.25 (1H, m), 5.15-5.32 (1H, br), 7.20-7.27 (2H, m), 7.31-7.37 (2H,m), 9.10 (1H, brs), 9.68 (1H, brm). 1023 —H —F —OCF3 —H —H 1H-NMR (DMSO-2 Hydrochloride d6) δ ppm: 1.04- 1.20 (1H, m), 1.20- 1.41 (5H, m),1.479- 1.78 (7H, m), 1.97- 2.07 (1H, m), 2.86- 3.11 (3H, m), 3.15- 3.27(1H, m), 4.45- 6.85 (1H, br), 7.00- 7.16 (1H, m), 7.22- 7.29 (1H, m),7.46- 7.55 (1H, m), 9.12 (1H, brs), 9.77 (1H, brs). 1024 —H —H —OCHF2 —H—H 1H-NMR (DMSO- 2 Hydrochloride d6) δ ppm: 0.98- 1.40 (6H, m), 1.49-1.77 (7H, m), 1.95- 2.06 (1H, m), 2.76- 2.95 (2H, m), 3.03 (1H, d, J =12.3 Hz), 3.10-3.23 (1H, m), 6.20-6.90 (1H, br), 7.01 (0.25H, s),7.13-7.23 (4.5H, m), 7.38 (0.25H, s), 9.17 (1H, brs), 9.74 (1H, brm).1025 —H —F —OCHF2 —H —H 1H-NMR (DMSO- 2 Hydrochloride d6) δ ppm:1.03-1.40 (6H, m), 1.50-1.67 (6H, m), 1.67-1.77 (1H, m), 1.96-2.05 (1H,m), 2.81-2.95 (2H, m), 3.02 (1H, d, J = 12.5 Hz), 3.10- 3.23 (1H, m),3.88- 4.20 (1H, br), 6.96- 7.01 (1H, m), 7.02 (0.25H, s), 7.17 (1H, dd,J = 2.5, 12.1 Hz), 7.20 (0.5H, s) 7.33 (1H, t, J = 8.9 Hz), 7.39 (0.25H,s), 9.08-9.22 (1H, m), 9.70-9.88 (1H, m). 1026 —H —Cl —OCHF2 —H —H1H-NMR (DMSO- 2 Hydrochloride d6) δ ppm: 1.02- 1.15 (1H, m), 1.15- 1.41(5H, m), 1.50- 1.67 (6H, m), 1.67- 1.78 (1H, m), 1.93- 2.04 (1H, m),2.78- 2.95 (2H, m), 2.95- 3.06 (1H, m), 3.10- 3.25 (1H, m), 3.50- 4.05(1H, br), 7.15 (1H, dd, J = 2.5, 8.8 Hz), 7.24 (1H, t, J = 73.3 Hz),7.32 (1H, d, J = 2.5 Hz), 7.34 (1H, d, J = 8.8 Hz), 8.90-9.20 (1H, br),9.44-9.75 (1H, br). 1027 —H —OCHF2 —H —H —H 1H-NMR (DMSO- 2Hydrochloride d6) δ ppm: 1.01- 1.15 (1H, m), 1.15- 1.42 (5H, m), 1.50-1.68 (6H, m), 1.68- 1.78 (1H, m), 1.96- 2.06 (1H, m), 2.83- 2.96 (2H,m), 3.03 (1H, d, J = 12.7 Hz), 3.10-3.25 (1H, m), 6.89 (1H, s), 6.96(1H, dd, J = 2.1, 8.1 Hz), 7.00 (1H, d, J = 8.1 Hz), 7.27 (1H, t, J =74.1 Hz), 7.39 (1H, t, J = 8.1 Hz), 7.85-8.90 (1H, br), 9.00-9.25 (1H,br), 9.65-9.85 (1H, br). 1028 —H —OCHF2 —Cl —H —H 1H-NMR (DMSO- 2Hydrochloride d6) δ ppm: 1.02- 1.41 (6H, m), 1.49- 1.80 (7H, m), 1.91-2.07 (1H, m), 2.78- 2.90 (1H, m), 2.90- 3.05 (2H, m), 3.10- 3.27 (1H,m), 3.90- 4.65 (1H, br), 7.01- 7.08 (2H, m), 7.32 (1H, t, J = 73.3 Hz),7.54 (1H, d, J = 8.4 Hz), 8.85-9.10 (1H, m), 9.39-9.70 (1H, m). 1029 —H—OCHF2 —F —H —H 1H-NMR (DMSO- Hydrochloride d6) δ ppm: 1.00- 1.40 (6H,m), 1.47- 1.65 (6H, m), 1.67- 1.77 (1H, m), 1.90- 2.00 (1H, m), 2.70-2.80 (1H, m), 2.87 (1H, d, J = 12.5 Hz), 2.96 (1H, d, J = 12.5 Hz),3.10-3.24 (1H, m), 7.02-7.11 (2.25H, m), 7.27 (0.5H, s), 7.37 (1H, dd, J= 8.8, 10.5 Hz), 7.46 (0.25H, s), 8.80-9.00 (1H, br), 9.39-9.58 (1H,br). 1030 —H —CN —OCHF2 —H —H 1H-NMR (DMSO- 2 Hydrochloride d6) δ ppm:1.02- 1.15 (1H, m), 1.17- 1.40 (5H, m), 1.48- 1.81 (7H, m), 1.93- 2.07(1H, m), 2.82- 2.91 (1H, m), 2.94 (1H, d, J = 12.6 Hz), 3.01 (1H, d, J =12.6 Hz), 3.08-3.25 (1H, m), 3.70-4.20 (1H, br), 7.39 (1H, t, J = 72.6Hz), 7.42 (1H, d, J = 8.9 Hz), 7.51 (1H, dd, J = 2.7, 9.0 Hz), 7.69 (1H,d, J = 2.7 Hz), 8.90-9.10 (1H, br), 9.35-9.70 (1H, br). 1031 —H —F—OCHF2 —F —H 1H-NMR (DMSO- 2 Hydrochloride d6) δ ppm: 1.08- 1.40 (6H,m), 1.43- 1.80 (7H, m), 1.95- 2.07 (1H, m), 2.88- 2.99 (1H, m), 3.05(1H, d, J = 13.1 Hz), 3.09 (1H, d, J = 13.1 Hz), 3.17-3.30 (1H, m),3.48-3.70 (1H, br), 6.97-7.06 (2.25H, m), 7.19 (0.5H, s), 7.37 (0.25H,s), 8.81-9.04 (1H, br), 9.45-9.65 (1H, br). 1032 —H —H —OCH2CHF2 —H —H1H-NMR (DMSO- 2 Hydrochloride d6) δ ppm: 0.98- 1.85 (13H, m), 1.90- 2.20(1H, m), 2.60- 3.80 (4H, m), 4.20- 4.40 (2H, m), 4.40- 5.40 (1H, br),6.38 (1H, tt, J = 3.4, 54.5 Hz), 6.85-7.70 (4H, brm), 8.84-10.40 (2H,br). 1033 —H —F OCH2CHF2 —H —H 1H-NMR (CDCl3) — δ ppm: 0.94-1.11 (4H,m), 1.14-1.41 (7H, m), 1.57-1.78 (4H, m), 2.13-2.22 (1H, m), 2.56 (1H,d, J = 11.1 Hz), 2.70- 2.79 (2H, m), 4.21 (2H, dt, J = 4.2, 13.1 Hz),6.08 (1H, tt, J = 4.2, 55.1 Hz), 6.77- 6.83 (1H, m), 6.83- 6.95 (2H, m).1034 —H Cl OCH2CHF2 —H —H 1H-NMR (CDCl3) δ ppm: 0.93-1.11 (4H, m),1.15-1.41 (7H, m), 1.55-1.77 (4H, m), 2.14-2.23 (1H, m), 2.57 (1H, d, J= 11.0 Hz), 2.68- 2.78 (2H, m), 4.20 (2H, dt, J = 4.2, 13.0 Hz), 6.12(1H, tt, J = 4.2, 55.1 Hz), 6.87 (1H, d, J = 8.7 Hz), 6.96 (1H, dd, J =2.5, 8.7 Hz), 7.13 (1H, d, J = 2.5 Hz). 1035 —H —CH3 —OCHF2 —H —H 1H-NMR(DMSO- 2 Hydrochloride d6) δ ppm: 0.97- 1.10 (1H, m), 1.12- 1.40 (5H,m), 1.47- 1.63 (6H, m), 1.67- 1.76 (1H, m), 1.90- 2.01 (1H, m), 2.20(3H, m), 2.70-2.80 (1H, m), 2.83 (1H, d, J = 12.3 Hz), 2.95 (1H, d, J =12.3 Hz), 3.08-3.22 (1H, m), 4.60-5.40 (1H, br), 6.94 (0.25H, s), 6.99(1H, dd, J = 2.5, 8.5 Hz), 7.05 (1H, d, J = 2.5 Hz), 7.09-7.15 (1.5H,m), 7.31 (0.25H, s), 8.85-9.01 (1H, m), 9.40-9.55 (1H, m). 1036 —H —OCH3—OCHF2 —H —H 1H-NMR (DMSO- 2 Hydrochloride d6) δ ppm: 1.00- 1.40 (6H,m), 1.50- 1.80 (7H, m), 1.95- 2.06 (1H, m), 2.75- 2.94 (2H, m), 2.96-3.07 (1H, m), 3.09- 3.22 (1H, m), 3.82 (3H, s), 6.08-6.65 (1H, br), 6.73(1H, d, J = 8.2 Hz), 6.80- 6.89 (1.25H, m), 7.01 (0.5H, s), 7.14 (1H, d,J = 8.4 Hz), 7.19 (0.25H, s), 9.09 (1H, brs), 9.72 (1H, brs).

TABLE 118 absolute configuration

Example R⁴ NMR Salt 1037

1H-NMR (DMSO-d6) δ ppm: 1.1-1.35 (3H, m), 1.4-1.55 (1H, m), 1.55-1.95(8H, m), 1.95-2.05 (2H, m), 2.68 (1H, d, J = 11.9 Hz), 2.8-4.0 (5H, m),6.55 (1H, s), 6.85-6.95 (2H, m), 7.14-7.22 (2H, m). ½ Fumarate 1038

1H-NMR (CDCl3) δ ppm: 0.95-1.15 (2H, m), 1.3-1.4 (1H, m), 1.4-2.1 (11H,m), 2.25-2.4 (1H, m), 3.04 (1H, d, J = 11.1 Hz), 3.17 (1H, d, J = 10.9Hz), 3.41 (1H, br), 3.45-3.58 (1H, m), 6.54 (1H, dd, J = 3.3, 8.4 Hz),6.82 (1H, dd, J = 2.5, 2.5 Hz), 6.91 (1H, dd, J = 8.6, 10.4 Hz), 7.59(1H, d, J = 2.1 Hz). — 1039

1H-NMR (DMSO-d6) δ ppm: 0.95-1.5 (3H, m), 1.5-1.7 (2H, m), 1.7-2.3 (6H,m), 2.3-2.7 (3H, m), 3.0-3.4 (1H, m), 3.59 (2H, br), 3.73 (1H, br), 7.07(1H, br), 7.3-7.45 (1H, m), 7.48 (1H, d, J = 5.4 Hz), 7.64 (1H, br),7.75 (1H, d, J = 5.4 Hz), 8.75-10.3 (2H, m). Hydrochloride

TABLE 119 absolute configuration

Example R⁴ NMR Salt 1040

1H-NMR (DMSO-d6) δ ppm: 1.1-1.35 (3H, m), 1.4-1.55 (1H, m), 1.55-1.95(8H, m), 1.95-2.05 (2H, m), 2.68 (1H, d, J = 11.9 Hz), 2.8-4.0 (5H, m),6.55 (1H, s), 6.85-6.95 (2H, m), 7.14-7.22 (2H, m). ½ Fumarate 1041

1H-NMR (CDCl3) δ ppm: 0.95-1.1 (2H, m), 1.3-1.4 (1H, m), 1.4-2.1 (11H,m), 2.25-2.4 (1H, m), 3.01 (1H, d, J = 11.0 Hz), 3.17 (1H, d, J = 11.1Hz), 3.40 (1H, br), 3.45-3.5 (1H, m), 3.97 (3H, s), 6.58 (1H, d, J = 8.4Hz), 6.70 (1H, d, J = 8.4 Hz), 6.80 (1H, d, J = 2.1 Hz), 7.58 (1H, d, J= 2.1 Hz). — 1042

1H-NMR (CDCl3) δ ppm: 0.95-1.15 (2H, m), 1.3-1.4 (1H, m), 1.4-2.1 (11H,m), 2.25-2.4 (1H, m), 3.04 (1H, d, J = 11.1 Hz), 3.17 (1H, d, J = 10.9Hz), 3.41 (1H, br), 3.45-3.58 (1H, m), 6.54 (1H, dd, J = 3.3, 8.4 Hz),6.82 (1H, dd, J = 2.5, 2.5 Hz), 6.91 (1H, dd, J = 8.6, 10.4 Hz), 7.59(1H, d, J = 2.1 Hz). — 1043

1H-NMR (DMSO-d6) δ ppm: 0.95-1.5 (3H, m), 1.5-1.7 (2H, m), 1.7-2.3 (6H,m), 2.3-2.7 (3H, m), 3.0-3.4 (1H, m), 3.59 (2H, br), 3.73 (1H, br), 7.07(1H, br), 7.3-7.45 (1H, m), 7.48 (1H, d, J = 5.4 Hz), 7.64 (1H, br),7.75 (1H, d, J = 5.4 Hz), 8.75-10.3 (2H, m). Hydrochloride

TABLE 120 absolute configuration

Example R⁴ NMR Salt 1044

1H-NMR (CDCl3) δ ppm: 0.90-2.30 (10H, m), 2.36-3.40 (7H, m), 3.50-3.70(1H, m), 7.30- 7.55 (3H, m), 7.55-7.75 (1H, m), 7.75-7.90 (3H, m),9.75-10.40 (2H, br). 2 Hydrochloride

TABLE 121 absolute configuration

Example R⁴ NMR Salt 1045

1H-NMR (DMSO-d6) δ ppm: 0.85-1.0 (1H, m), 1.12-1.40 (2H, m), 1.42-1.63(3H, m), 1.65-1.78 (1H, m), 1.84-1.97 (3H, m), 1.97- 2.06 (1H, m),2.24-2.38 (2H, m), 2.39-2.49 (1H, m), 2.73-2.93 (2H, m), 3.03 (1H, d, J= 12.5 Hz), 3.23 (1H, d, J = 12.5 Hz), 3.6 (1H, br), 7.15-7.25 (2H, m),7.37-7.46 (2H, m), 9.37 (1H, br), 9.87 (1H, br). 2 Hydrochloride 1046

1H-NMR (CDCl3) δ ppm: 0.95-1.1 (1H, m), 1.15-1.45 (3H, m), 1.45-1.95(10H, m), 2.45- 2.7 (3H, m), 2.80 (1H, dd, J = 1.7, 11.2 Hz), 3.19 (1H,d, J = 11.1 Hz), 3.91 (3H, s), 7.08- 7.15 (2H, m), 7.29 (1H, dd, J =2.1, 8.7 Hz), 7.45 (1H, d J = 2.0 Hz), 7.63-7.71 (2H, m). — 1047

1H-NMR (DMSO-d6) δ ppm: 0.85-1.1 (1H, m), 1.1-1.45 (2H, m), 1.45-1.65(3H, m), 1.65-1.8 (1H, m), 1.8-2.0 (3H, m), 2.0-2.15 (1H, m), 2.25-2.65(3H, m), 2.85-3.35 (2H, m), 3.6-4.35 (3H, m), 6.9-7.2 (2H, m), 7.31 (1H,dd, J = 8.0, 8.0 Hz), 7.46 (1H, d, J = 8.2 Hz), 8.00 (1H, d, J = 1.6Hz), 9.3-10.3 (2H, m). 2 Hydrochloride 1048

1H-NMR (DMSO-d6) δ ppm: 0.8-1.0 (1H, m), 1.1-1.6 (5H, m), 1.6-2.0 (5H,m), 2.1-2.5 (3H, m), 2.75-2.95 (2H, m), 2.95-3.13 (1H, m), 3.17 (1H, d,J = 12.6 Hz), 6.56 (4H, s), 6.99-7.14 (2H, m), 7.20 (1H, dd, J = 8.6,10.7 Hz), 8.09 (1H, d, J = 2.0 Hz), 11.4 (5H, br). 2 Fumarate

TABLE 122 absolute configuration

Example R⁴ NMR Salt 1049

1H-NMR (DMSO-d6) δ ppm: 0.85-1.05 (1H, m), 1.1-1.4 (2H, m), 1.4-1.65(3H, m), 1.65- 1.8 (1H, m), 1.8-2.0 (3H, m), 2.0-2.1 (1H, m), 2.25-2.4(2H, m), 2.4-2.6 (1H, m), 2.75- 2.95 (2H, m), 3.0-3.1 (1H, m), 3.23 (1H,d, J = 12.6 Hz), 3.5-4.0 (1H, m), 7.15-7.25 (2H, m), 7.35-7.45 (2H, m),9.3-9.6 (1H, m), 9.85-10.1 (1H, m). 2 Hydrochloride 1050

1H-NMR (CDCl3) δ ppm: 0.95-1.1 (1H, m), 1.1-1.45 (3H, m), 1.45-1.95(10H, m), 2.45- 2.7 (3H, m), 2.80 (1H, dd, J = 1.7, 11.2 Hz), 3.19 (1H,d, J = 11.2 Hz), 3.91 (3H, s), 7.07- 7.15 (2H, m), 7.29 (1H, dd, J =2.1, 8.7 Hz), 7.45 (1H, d, J = 2.0 Hz), 7.63-7.71 (2H, m). — 1051

1H-NMR (DMSO-d6) δ ppm: 0.85-1.1 (1H, m), 1.1-1.4 (2H, m), 1.4-1.65 (3H,m), 1.65- 1.8 (1H, m), 1.8-2.0 (3H, m), 2.0-2.15 (1H, m), 2.25-2.65 (3H,m), 2.8-3.45 (2H, m), 3.5-4.25 (3H, m), 6.9-7.2 (2H, m), 7.31 (1H, dd, J= 8.0, 8.0 Hz), 7.46 (1H, d, J = 8.2 Hz), 8.00 (1H, d, J = 1.8 Hz),9.3-10.3 (2H, m). 2 Hydrochloride 1052

1H-NMR (DMSO-d6) δ ppm: 0.8-0.95 (1H, m), 1.1-1.4 (3H, m), 1.45-1.6 (2H,m), 1.6- 1.7 (1H, m), 1.7-1.9 (4H, m), 2.0-2.15 (1H, m), 2.15-2.3 (1H,m), 2.35-2.5 (1H, m), 2.65-2.85 (2H, m), 2.85-3.0 (1H, m), 3.13 (1H, d,J = 11.7 Hz), 6.53 (3H, s), 7.0-7.1 (2H, m), 7.18 (1H, dd, J = 8.6, 10.8Hz), 8.07 (1H, d, J = 2.1 Hz), 10.3 (4H, br). 1.5 Fumarate

TABLE 123 absolute configuration

Example R⁴ NMR Salt 1053

1H-NMR (CDCl3) δ ppm: 1.14-1.29 (1H, m), 1.29-1.38 (1H, m), 1.38-1.58(3H, m), 1.62- 1.86 (4H, m), 2.95-3.05 (2H, m), 3.1-3.25 (3H, m),3.6-3.7 (1H, m), 6.74-6.82 (2H, m), 7.14-7.21 (2H, m). — 1054

1H-NMR (CDCl3) δ ppm: 1.14-1.36 (2H, m), 1.37-1.65 (3H, m), 1.65-1.77(2H, m), 1.77- 1.91 (2H, m), 3.01-3.17 (2H, m), 3.19-3.28 (3H, m),3.75-3.83 (1H, m), 3.88 (3H, s), 6.97-7.11 (3H, m), 7.23-7.30 (1H, m),7.57 (1H, d, J = 8.8 Hz), 7.62 (1H, d, J = 0.9 Hz). — 1055

1H-NMR (DMSO-d6) δ ppm: 0.97-1.14 (2H, m), 1.32-1.43 (1H, m), 1.43-1.67(2H, m), 1.68-2.03 (3H, m), 3.01-3.14 (2H, m), 3.25- 3.43 (2H, m),3.55-3.64 (1H, m), 3.66-3.77 (1H, m), 6.55 (4H, s), 6.68 (1H, br), 7.10(1H, dd, J = 8.7, 10.7 Hz), 7.22 (1H, br), 8.05 (1H, d, J = 2.2 Hz),11.27 (5H, br). 2 Fumarate 1056

1H-NMR (DMSO-d6) δ ppm: 0.95-1.15 (2H, m), 1.28-1.40 (1H, m), 1.43-1.72(3H, m), 1.94 (2H, br), 2.90-3.12 (2H, m), 3.19-3.30 (1H, m), 3.34-3.57(2H, m), 3.70-3.87 (1H, br), 6.53 (2H, s), 7.00 (1H, br), 7.34 (1H, dd,J = 7.7, 7.7 Hz), 7.45 (1H, d, J = 5.4 Hz), 7.5-7.65 (1H, m), 7.72 (1H,d, J = 5.4 Hz), 10.5 (3H, br). Fumarate 1057

1H-NMR (CDCl3) δ ppm: 0.96-1.18 (2H, m), 1.33-1.72 (5H, m), 1.72-1.91(1H, m), 1.92- 2.07 (1H, m), 2.82-2.92 (1H, m), 3.03-3.17 (1H, m),3.17-3.27 (1H, m), 3.38 (1H, br), 3.42-3.52 (1H, m), 3.52-3.61 (1H, m),6.85 (1H, d, J = 7.6 Hz), 7.21-7.28 (1H, m), 7.37 (1H, d, J = 5.5 Hz),7.40-7.47 (1H, m), 7.52 (1H, d, J = 8.0 Hz). — 1058

1H-NMR (DMSO-d6) δ ppm: 1.26-1.42 (2H, m), 1.42-1.63 (2H, m), 1.63-1.91(3H, m), 1.91-2.04 (1H, m), 3.01-3.18 (2H, m), 3.24- 3.42 (1H, m),3.47-3.55 (1H, m), 3.55-3.65 (1H, m), 4.06-4.19 (1H, m), 6.95 (1H, dd, J= 2.9, 9.0 Hz), 7.18 (1H, d, J = 2.9 Hz), 7.43 (1H, d, J = 9.0 Hz), 9.00(1H, br), 9.62 (1H, br). Hydrochloride 1059

1H-NMR (DMSO-d6) δ ppm: 0.9-1.15 (2H, m), 1.25-1.4 (1H, m), 1.4-1.7 (3H,m), 1.91 (2H, br), 2.82-2.92 (1H, m), 2.97-3.10 (1H, m), 3.15-3.60 (7H,m), 6.52 (2H, s), 6.94 (1H, br), 7.15 (1H, dd, J = 8.9, 8.9 Hz), 7.59(1H, br), 7.83 (1H, d, J = 5.3 Hz). Fumarate 1060

1H-NMR (DMSO-d6) δ ppm: 1.0-1.15 (2H, m), 1.28-1.40 (1H, m), 1.4-1.65(2H, m), 1.65-1.77 (1H, m), 1.78-1.98 (2H, m), 2.95- 3.15 (2H, m),3.15-3.25 (1H, m), 3.25-3.4 (1H, m), 3.43 (1H, br), 3.7-3.8 (1H, m),6.53 (2H, s), 6.68 (1H, d, J = 8.5 Hz), 7.19 (1H, bs), 7.26 (1H, d, J =8.4 Hz), 8.04 (1H, d, J = 2.2 Hz). Fumarate 1061

1H-NMR (DMSO-d6) δ ppm: 1.17-1.32 (2H, m), 1.34-1.56 (2H, m), 1.59-1.85(3H, m), 1.86-1.96 (1H, m), 2.95-3.14 (2H, m), 3.23- 3.40 (3H, m),3.90-3.99 (1H, m), 6.51 (2H, s), 7.13 (1H, dd, J = 2.3, 8.9 Hz),7.27-7.34 (2H, m), 7.66 (1H, d, J = 5.4 Hz), 7.80 (1H, d, J = 8.9 Hz).Fumarate 1062

1H-NMR (DMSO-d6) δ ppm: 1.16-1.40 (3H, m), 1.40-1.55 (1H, m), 1.57-1.73(2H, m), 1.73-1.87 (2H, m), 2.85-3.03 (3H, m), 3.04- 3.83 (4H, m),3.85-3.93 (1H, m), 6.49 (1H, s), 7.09 (1H, dd, J = 2.2, 8.9 Hz), 7.25(1H, d, J = 5.3 Hz), 7.35-7.41 (2H, m), 7.67 (1H, d, J = 8.8 Hz). ½Fumarate

TABLE 124 absolute configuration

Example R⁴ NMR Salt 1063

1H-NMR (CDCl3) δ ppm: 1.23-1.43 (3H, m), 1.44-1.57 (1H, m), 1.58-1.72(1H, m), 1.74- 1.84 (1H, m), 2.08-2.27 (2H, m), 2.33-2.42 (1H, m),2.72-2.79 (1H, m), 2.86-2.93 (1H, m), 2.97 (1H, d, J = 13.2 Hz),3.14-3.25 (2H, m), 3.81-3.90 (4H, m), 4.22 (1H, d, J = 13.1 Hz), 6.97(1H, bs), 7.02-7.09 (2H, m), 7.22-7.30 (2H, m), 7.31-7.38 (2H, m), 7.38-7.43 (2H, m), 7.55 (1H, d, J = 8.7 Hz), 7.61 (1H, d, J = 0.9 Hz). — 1064

1H-NMR (CDCl3) δ ppm: 1.0-1.2 (2H, m), 1.2-1.4 (1H, m), 1.4-1.9 (3H, m),2.0-2.5 (3H, m), 2.75-3.2 (4H, m), 3.38 (1H, br), 3.60 (1H, br), 3.96(3H, s), 4.19 (1H, br), 6.54 (1H, br), 6.68 (1H, d, J = 8.2 Hz), 6.82(1H, br), 7.22-7.29 (1H, m), 7.29-7.38 (2H, m), 7.38-7.44 (2H, m), 7.58(1H, d, J = 2.2 Hz). —

TABLE 125 absolute configuration

Example R⁴ NMR Salt 1065

1H-NMR (CDCl3) δ ppm: 1.15-1.56 (5H, m), 1.65-1.76 (2H, m), 1.76-1.90(2H, m), 3.01- 3.18 (2H, m), 3.20-3.28 (3H, m), 3.76-3.83 (1H, m), 3.88(3H, s), 7.01 (1H, d, J = 2.4 Hz), 7.04 (1H, d, J = 2.5 Hz), 7.07 (1H,dd, J = 2.6, 8.8 Hz), 7.25 (1H, dd, J = 2.5, 9.0 Hz), 7.57 (1H, d, J =8.8 Hz), 7.62 (1H, d, J = 9.0 Hz) — 1066

1H-NMR (DMSO-d6) δ ppm: 0.93-1.22 (2H, m), 1.33-1.47 (1H, m), 1.47-1.70(1H, m), 1.70-1.94 (2H, m), 1.94-2.19 (1H, m), 2.88- 3.22 (2H, m),3.27-3.48 (2H, m), 3.59-3.78 (2H, m), 3.86 (3H, s), 6.69 (1H, br), 6.82(1H, d, J = 8.3 Hz), 7.13 (1H, d, J = 1.9 Hz), 7.95 (1H, d, J = 2.1 Hz),8.5 (1H, br), 9.00 (1H, br), 9.68 (1H, br). 2 Hydrochloride

TABLE 126 absolute configuration

Example R⁴ NMR Salt 1067

1H-NMR (CDCl3) δ ppm: 1.22-1.43 (3H, m), 1.45-1.56 (1H, m), 1.58-1.72(1H, m), 1.74- 1.84 (1H, m), 2.08-2.27 (2H, m), 2.32-2.42 (1H, m),2.73-2.79 (1H, m), 2.86-2.93 (1H, m), 2.97 (1H, d, J = 13.1 Hz),3.14-3.25 (2H, m), 3.8-3.9 (4H, m), 4.22 (1H, d, J = 13.2 Hz), 6.97 (1H,bs), 7.02-7.09 (2H, m), 7.22-7.30 (2H, m), 7.31-7.37 (2H, m), 7.37- 7.43(2H, m), 7.55 (1H, d, J = 8.7 Hz), 7.61 (1H, d, J = 9.0 Hz). — 1068

1H-NMR (CDCl3) δ ppm: 1.0-1.2 (2H, m), 1.2-1.4 (1H, m), 1.4-1.85 (3H,m), 2.05-2.5 (3H, m), 2.65-3.15 (4H, m), 3.2-3.5 (1H, m), 3.60 (1H, br),3.96 (3H, s), 4.05-4.4 (1H, m), 6.54 (1H, br), 6.68 (1H, d, J = 8.2 Hz),6.82 (1H, br), 7.22-7.29 (1H, m), 7.29-7.38 (2H, m), 7.38-7.44 (2H, m),7.58 (1H, d, J = 2.2 Hz). —

TABLE 127 absolute configuration

Example R⁴ NMR Salt 1069

1H-NMR (CDCl3) δ ppm: 1.15-1.56 (5H, m), 1.65-1.76 (2H, m), 1.76-1.89(2H, m), 3.00- 3.20 (2H, m), 3.20-3.28 (3H, m), 3.76-3.83 (1H, m), 3.88(3H, s), 7.01 (1H, d, J = 2.4 Hz), 7.04 (1H, d, J = 2.4 Hz), 7.07 (1H,dd, J = 2.6, 8.8 Hz), 7.26 (1H, dd, J = 2.5, 9.0 Hz), 7.57 (1H, d, J =8.8 Hz), 7.62 (1H, d, J = 9.0 Hz). — 1070

1H-NMR (DMSO-d6) δ ppm: 0.94-1.19 (2H, m), 1.35-1.47 (1H, m), 1.47-1.70(1H, m), 1.70-1.91 (2H, m), 1.91-2.18 (1H, m), 3.0- 3.25 (2H, m),3.25-3.55 (2H, m), 3.6-3.8 (2H, m), 3.88 (3H, s), 6.69 (1H, br), 6.82(1H, d, J = 8.4 Hz), 7.13 (1H, d, J = 2.2 Hz), 7.95 (1H, d, J = 2.1 Hz),8.90 (1H, br), 9.56 (1H, br). Hydrochloride

TABLE 128 absolute configuration

Example R⁴ NMR Salt 1071

1H-NMR (CDCl3) δ ppm: 0.96-1.19 (19H, m), 1.19-1.41 (6H, m), 1.50-1.67(2H, m), 1.67- 1.82 (3H, m), 2.48-2.65 (2H, m), 2.94-3.09 (2H, m),3.09-3.25 (2H, m), 7.09 (1H, dd, J = 2.4, 8.9 Hz), 7.17 (1H, d, J = 2.4Hz), 7.28 (1H, dd, J = 2.1, 11.0 Hz), 7.45 (1H, d, J = 2.0 Hz),7.59-7.66 (2H, m). — 1072

1H-NMR (CDCl3) δ ppm: 0.95-1.09 (1H, m), 1.14 (18H, d, J = 7.5 Hz),1.20-1.45 (3H, m), 1.48-1.85 (8H, m), 2.58-2.74 (2H, m), 2.90- 3.00 (1H,m), 3.00-3.08 (1H, m), 3.17-3.30 (2H, m), 6.74 (1H, dd, J = 0.7, 3.2Hz), 6.85 (1H, d, J = 7.3 Hz), 7.03-7.10 (1H, m), 7.17 (1H, d, J = 3.2Hz), 7.26 (1H, d, J = 8.3 Hz). — 1073

1H-NMR (CDCl3) δ ppm: 0.95-1.09 (1H, m), 1.09-1.42 (21H, m), 1.53-1.80(8H, m), 2.41- 2.50 (1H, m), 2.54-2.64 (1H, m), 2.95-3.10 (3H, m),3.13-3.23 (1H, m), 6.56 (1H, d, J = 0.4, 3.1 Hz), 6.97 (1H, dd, J = 2.1,8.8 Hz), 7.23 (1H, d, J = 3.1 Hz), 7.37-7.44 (2H, m). — 1074

1H-NMR (CDCl3) δ ppm: 0.94-1.06 (1H, m), 1.05-1.25 (19H, m), 1.25-1.45(2H, m), 1.53- 1.80 (8H, m), 2.42-2.50 (1H, m), 2.55-2.65 (1H, m),2.90-3.00 (1H, m), 3.00-3.13 (2H, m), 3.16- 3.25 (1H, m), 6.56 (1H, dd,J = 0.7, 3.2 Hz), 6.97 (1H, dd, J = 1.7, 8.3 Hz), 7.20 (1H, d, J = 3.2Hz), 7.32 (1H, s), 7.52 (1H, d, J = 8.3 Hz). —

TABLE 129 absolute configuration

Example R⁴ NMR Salt 1075

1H-NMR (CDCl3) δ ppm: 0.95-1.09 (1H, m), 1.20-1.55 (4H, m), 1.55-1.63(1H, m), 1.66- 1.86 (3H, m), 2.59-2.77 (2H, m), 2.81-3.01 (1H, m),3.01-3.09 (1H, m), 3.18-3.30 (2H, m), 6.66- 6.71 (1H, m), 6.87 (1H, dd,J = 1.1, 7.2 Hz), 7.10-7.21 (3H, m), 8.25 (1H, brs). — 1076

1H-NMR (CDCl3) δ ppm: 0.96-1.10 (1H, m), 1.10-1.43 (3H, m), 1.43-1.65(3H, m), 1.65- 1.84 (2H, m), 2.42-2.53 (1H, m), 2.53-2.66 (1H, m),2.97-3.12 (3H, m), 3.15-3.26 (1H, m), 6.51 (1H, dd, J = 1.0, 2.1 Hz),7.06 (1H, dd, J = 2.0, 8.6 Hz), 7.17-7.23 (1H, m), 7.32 (1H, d, J = 8.6Hz), 7.44 (1H, d, J = 2.0 Hz), 8.36 (1H, brs). — 1077

1H-NMR (DMSO-d6) δ ppm: 0.81-0.96 (1H, m), 1.06-1.35 (3H, m), 1.43-1.57(2H, m), 1.58- 1.74 (2H, m), 2.01 (1H, brs), 2.30-2.41 (2H, m),2.75-2.97 (4H, m), 6.31-6.37 (1H, m), 6.80 (1H, dd, J = 1.8, 8.4 Hz),7.10 (1H, s), 7.25 (1H, t, J = 2.7 Hz), 7.41 (1H, d, J = 8.4 Hz), 10.89(1H, s). — 1078

1H-NMR (DMSO-d6) δ ppm: 0.85-0.98 (1H, m), 1.12-1.35 (3H, m), 1.48-1.73(4H, m), 2.17 (1H, brs), 2.32-2.50 (2H, m), 2.76-3.01 (4H, m), 6.99-7.08(2H, m), 7.20 (1H, dd, J = 2.1, 8.7 Hz), 7.41 (1H, d, J = 1.8 Hz), 7.58(1H, d, J = 8.8 Hz), 7.67 (1H, d, J = 8.8 Hz), 9.56 (1H, brs). —

TABLE 130 absolute configuration

Example R⁴ NMR Salt 1079

1H-NMR (CDCl3) δ ppm: 1.00-1.14 (1H, m), 1.20-1.45 (3H, m), 1.45-1.60(1H, m), 1.60- 1.68 (1H, m), 1.68-1.85 (3H, m), 2.53-2.66 (2H, m),2.95-3.10 (2H, m), 3.15-3.26 (2H, m), 7.33 (1H, dd, J = 2.1, 8.8 Hz),7.37-7.47 (2H, m), 7.51 (1H, d, J = 2.1 Hz), 7.74-7.82 (3H, m). — 1080

1H-NMR (CDCl3) δ ppm: 0.98-1.12 (1H, m), 1.17-1.82 (8H, m), 2.48-2.64(2H, m), 2.95- 3.25 (4H, m), 3.90 (3H, s), 7.08-7.14 (2H, m), 7.31 (1H,dd, J = 2.1, 8.7 Hz), 7.47 (1H, d, J = 2.0 Hz), 7.63-7.70 (2H, m). —1081

1H-NMR (CDCl3) δ ppm: 0.97-1.10 (1H, m), 1.15-1.69 (6H, m), 1.69-1.84(2H, m), 2.45- 2.54 (1H, m), 2.54-2.63 (1H, m), 2.93-3.13 (3H, m),3.13-3.25 (1H, m), 7.19 (1H, dd, J = 2.0, 8.6 Hz), 5.27 (1H, d, J = 5.4Hz), 7.42 (1H, d, J = 5.4 Hz), 7.59 (1H, d, J = 2.0 Hz), 7.79 (1H, d, J= 8.6 Hz). — 1082

1H-NMR (DMSO-d6) δ ppm: 0.95-1.22 (2H, m), 1.22-1.37 (1H, m), 1.39-1.51(1H, m), 1.51- 1.68 (2H, m), 1.68-1.78 (1H, m), 1.99-2.11 (1H, m),2.92-3.75 (6H, brm), 4.30-5.75 (1H, br), 7.00-7.30 (2H, m), 7.30-7.52(1H, m), 8.15 (1H, s), 9.45-10.15 (2H, brm). 2 Hydrochloride 1083

1H-NMR (DMSO-d6) δ ppm: 0.90-1.05 (1H, m), 1.10-1.38 (2H, m), 1.49-1.66(3H, m), 1.67- 1.78 (1H, m), 1.96-2.08 (1H, m), 2.94-3.10 (1H, m),3.10-3.42 (5H, m), 3.53-4.15 (1H, br), 7.08 (1H, d, J = 8.3 Hz), 7.21(1H, brs), 7.40 (1H, d, J = 8.3 Hz), 8.12 (1H, d, J = 2.1 Hz), 9.51 (2H,brs). 2 Hydrochloride 1084

1H-NMR (DMSO-d6) δ ppm: 1.10-1.52 (4H, m), 1.52-1.69 (2H, m), 1.69-1.81(1H, m), 2.03- 2.22 (1H, m), 3.20-4.30 6H, m), 7.05 (1H, s), 7.25-7.70(1H, m), 7.70-8.05 (2H, m), 8.14 (1H, s), 9.60-10.47 (2H, m). (1H notfound) 2 Hydrochloride 1085

1H-NMR (CDCl3) δ ppm: 1.00-1.13 (1H, m), 1.19-1.45 (3H, m), 1.58-1.90(5H, m), 2.52- 2.62 (2H, m), 2.95-3.25 (4H, m), 7.22 (1H, dt, J = 2.5,8.8 Hz), 7.36 (1H, dd, J = 2.0, 8.8 Hz), 7.40 (1H, dd, J = 2.5, 9.9 Hz),7.51 (1H, d, J = 2.0 Hz), 7.69-7.78 (2H, m). — 1086

1H-NMR (DMSO-d6) δ ppm: 0.79-0.97 (1H, m), 1.05-1.56 (4H, m), 1.56-1.72(2H, m), 1.77- 1.90 (1H, m), 2.62-2.75 (1H, m), 2.79-3.19 (5H, m),3.19-3.70 (1H, br), 3.75 (3H, s), 6.37-6.56 (2H, m), 6.78 (1H, d, J =7.2 Hz), 7.30-7.14 (1H, m), 7.14-7.33 (2H, m). Fumarate 1087

1H-NMR (DMSO-d6) δ ppm: 0.86-1.00 (1H, m), 1.04-1.47 (4H, m), 1.47-1.57(1H, m), 1.61- 1.71 (1H, m), 1.77-1.86 (1H, m), 2.55-2.72 (2H, m),2.92-3.16 (4H, m), 3.75 (3H, s), 5.25-6.25 (1H, br), 6.35 (1H, dd, J =0.4, 3.0 Hz), 6.96 (1H, dd, J = 1.9, 8.6 Hz), 7.25-7.33 (2H, m), 7.35(1H, d, J = 8.6 Hz). (2H not found) Oxalate 1088

1H-NMR (CDCl3) δ ppm: 0.95-1.11 (1H, m), 1.11-1.42 (3H, m), 1.53-1.82(5H, m), 2.45-2.55 (1H, m), 2.55-2.64 (1H, m), 2.98-3.12 (3H, m),3.15-3.25 (1H, m), 3.75 (3H, s), 6.43 (1H, dd, J = 0.8, 3.1 Hz),6.98-7.03 (2H, m), 7.12-7.15 (1H, m), 7.53 (1H, d, J = 8.4 Hz). — 1089

1H-NMR (DMSO-d6) δ ppm: 0.87-1.02 (1H, m), 1.08-1.50 (4H, m), 1.50-1.60(1H, m), 1.62- 1.72 (1H, m), 1.75-1.86 (1H, m), 2.57-2.76 (2H, m),2.92-3.16 (4H, m), 3.20-4.38 (1H, br), 6.91 (1H, s), 7.09 (1H, dd, J =1.9, 8.5 Hz), 7.41 (1H, d, J = 1.9 Hz), 7.52 (1H, d, J = 8.5 Hz), 7.97(1H, d, J = 1.8 Hz). (2H not found) Oxalate

TABLE 131 absolute configuration

Example R⁴ NMR Salt 1090

1H-NMR (CDCl3) δ ppm: 0.99-1.18 (19H, m), 1.20-1.41 (6H, m), 1.49-1.68(2H, m), 1.68- 1.82 (3H, m), 2.49-2.64 (2H, m), 2.94-3.10 (2H, m),3.10-3.25 (2H, m), 7.09 (1H, dd, J = 2.4, 8.8 Hz), 7.17 (1H, d, J = 2.4Hz), 7.28 (1H, dd, J = 2.1, 11.0 Hz), 7.45 (1H, d, J = 2.0 Hz),7.59-7.66 (2H, m). — 1091

1H-NMR (CDCl3) δ ppm: 0.93-1.10 (1H, m), 1.14 (18H, d, J = 7.5 Hz),1.20-1.45 (3H, m), 1.49-1.85 (8H, m), 2.58-2.74 (2H, m), 2.90- 3.00 (1H,m), 3.00-3.08 (1H, m), 3.17-3.30 (2H, m), 6.74 (1H, dd, J = 0.7, 3.2Hz), 6.85 (1H, d, J = 7.3 Hz), 7.03-7.10 (1H, m), 7.17 (1H, d, J = 3.2Hz), 7.26 (1H, d, J = 8.3 Hz). — 1092

1H-NMR (CDCl3) δ ppm: 0.95-1.10 (1H, m), 1.10-1.41 (21H, m), 1.53-1.80(8H, m), 2.41- 2.50 (1H, m), 2.53-2.62 (1H, m), 2.95-3.10 (3H, m),3.13-3.23 (1H, m), 6.56 (1H, d, J = 0.4, 3.1 Hz), 6.97 (1H, dd, J = 2.1,8.8 Hz), 7.23 (1H, d, J = 3.1 Hz), 7.37-7.44 (2H, m). — 1093

1H-NMR (CDCl3) δ ppm: 0.94-1.06 (1H, m), 1.05-1.25 (19H, m), 1.25-1.45(2H, m), 1.53- 1.80 (8H, m), 2.42-2.50 (1H, m), 2.55-2.65 (1H, m),2.90-3.00 (1H, m), 3.00-3.13 (2H, m), 3.16- 3.25 (1H, m), 6.56 (1H, dd,J = 0.7, 3.2 Hz), 6.97 (1H, dd, J = 1.7, 8.3 Hz), 7.20 (1H, d, J = 3.2Hz), 7.32 (1H, s), 7.52 (1H, d, J = 8.3 Hz). —

TABLE 132 absolute configuration

Example R⁴ NMR Salt 1094

1H-NMR (CDCl3) δ ppm: 0.95-1.09 (1H, m), 1.18-1.55 (4H, m), 1.55-1.63(1H, m), 1.66- 1.85 (3H, m), 2.59-2.77 (2H, m), 2.81-3.01 (1H, m),3.01-3.09 (1H, m), 3.18-3.30 (2H, m), 6.67- 6.71 (1H, m), 6.87 (1H, dd,J = 1.1, 7.2 Hz), 7.10-7.20 (3H, m), 8.15-8.47 (1H, br). — 1095

1H-NMR (CDCl3) δ ppm: 0.96-1.10 (1H, m), 1.11-1.43 (3H, m), 1.52-1.84(5H, m), 2.42-2.52 (1H, m), 2.54-2.64 (1H, m), 2.97-3.10 (3H, m),3.14-3.25 (1H, m), 6.51 (1H, dd, J = 1.0, 2.1 Hz), 7.06 (1H, dd, J =2.0, 8.6 Hz), 7.17-7.23 (1H, m), 7.32 (1H, d, J = 8.6 Hz), 7.44 (1H, d,J = 2.0 Hz), 8.20 (1H, brs). — 1096

1H-NMR (DMSO-d6) δ ppm: 0.81-0.95 (1H, m), 1.05-1.35 (3H, m), 1.41-1.57(2H, m), 1.58- 1.74 (2H, m), 2.05 (1H, brs), 2.30-2.41 (2H, m),2.75-2.97 (4H, m), 6.30-6.38 (1H, m), 6.80 (1H, dd, J = 1.8, 8.4 Hz),7.10 (1H, s), 7.25 (1H, t, J = 2.7 Hz), 7.41 (1H, d, J = 8.4 Hz), 10.89(1H, s). — 1097

1H-NMR (DMSO-d6) δ ppm: 0.85-0.99 (1H, m), 1.12-1.36 (3H, m), 1.48-1.76(4H, m), 2.17 (1H, brs), 2.31-2.50 (2H, m), 2.76-3.01 (4H, m), 6.99-7.08(2H, m), 7.20 (1H, dd, J = 2.0, 8.7 Hz), 7.41 (1H, d, J = 1.6 Hz), 7.58(1H, d, J = 8.8 Hz), 7.67 (1H, d, J = 8.8 Hz), 9.57 (1H, brs). —

TABLE 133 absolute configuration

Example R⁴ NMR Salt 1098

1H-NMR (CDCl3) δ ppm: 1.00-1.14 (1H, m), 1.20-1.45 (3H, m), 1.45-1.68(2H, m), 1.68- 1.85 (3H, m), 2.53-2.66 (2H, m), 2.95-3.10 (2H, m),3.15-3.26 (2H, m), 7.33 (1H, dd, J = 2.1, 8.8 Hz), 7.37-7.47 (2H, m),7.51 (1H, d, J = 2.1 Hz), 7.74-7.82 (3H, m). — 1099

1H-NMR (CDCl3) δ ppm: 0.98-1.12 (1H, m), 1.17-1.45 (3H, m), 1.45-1.85(5H, m), 2.49- 2.64 (2H, m), 2.95-3.25 (4H, m), 3.90 (3H, s), 7.08-7.14(2H, m), 7.31 (1H, dd, J = 2.1, 8.7 Hz), 7.47 (1H, d, J = 2.0 Hz),7.63-7.70 (2H, m). — 1100

1H-NMR (CDCl3) δ ppm: 0.97-1.10 (1H, m), 1.15-1.69 (6H, m), 1.69-1.84(2H, m), 2.45- 2.54 (1H, m), 2.54-2.63 (1H, m), 2.93-3.13 (3H, m),3.13-3.25 (1H, m), 7.19 (1H, dd, J = 2.0, 8.6 Hz), 5.7 (1H, d, J = 5.4Hz), 7.42 (1H, d, J = 5.4 Hz), 7.59 (1H, d, J = 2.0 Hz), 7.79 (1H, d, J= 8.6 Hz). — 1101

1H-NMR (DMSO-d6) δ ppm: 0.91-1.10 (1H, m), 1.10-1.37 (2H, m), 1.41-1.66(3H, m), 1.66- 1.79 (1H, m), 1.06-2.09 (1H, m), 2.95-3.55 (6H, m),3.70-4.95 (1H, br), 7.00-7.17 (1H, m), 7.17- 7.40 (2H, m), 8.08-8.19(1H, m), 9.33-9.90 (2H, m). 2 Hydrochloride 1102

1H-NMR (DMSO-d6) δ ppm: 0.92-1.09 (1H, m), 1.10-1.39 (2H, m), 1.47-1.68(3H, m), 1.68- 1.78 (1H, m), 1.99-2.09 (1H, m), 2.94-3.14 (1H, br),3.14-3.50 (5H, brm), 4.05-5.03 (1H, br), 7.08-7.19 (1H, m), 7.25-7.36(1H, m), 7.41 (1H, d, J = 8.2 Hz), 8.14 (1H, d, J = 1.6 Hz), 9.70 (2H,brs). 2 Hydrochloride 1103

1H-NMR (DMSO-d6) δ ppm: 1.12-1.51 (4H, m), 1.53-1.68 (2H, m), 1.69-1.79(1H, m), 2.07- 2.19 (1H, m), 3.20-4.27 6H, m), 7.04 (1H, s), 7.30-7.65(1H, m), 7.65-8.05 (2H, m), 8.13 (1H, s), 9.65-10.40 (2H, m). (1H notfound) 2 Hydrochloride 1104

1H-NMR (CDCl3) δ ppm: 1.00-1.13 (1H, m), 1.18-1.45 (3H, m), 1.58-1.90(5H, m), 2.52- 2.65 (2H, m), 2.95-3.11 (2H, m), 3.11-3.25 (2H, m), 7.22(1H, dt, J = 2.5, 8.8 Hz), 7.36 (1H, dd, J = 2.0, 8.8 Hz), 7.40 (1H, dd,J = 2.5, 9.9 Hz), 7.51 (1H, d, J = 2.0 Hz), 7.69-7.78 (2H, m). — 1105

1H-NMR (DMSO-d6) δ ppm: 0.80-0.96 (1H, m), 1.05-1.56 (4H, m), 1.56-1.72(2H, m), 1.77- 1.90 (1H, m), 2.62-2.75 (1H, m), 2.77-2.90 (1H, m),2.90-3.19 (4H, m), 3.19-3.70 (1H, br), 3.75 (3H, s), 6.37-6.54 (2H, m),6.78 (1H, d, J = 7.3 Hz), 7.30-7.14 (1H, m), 7.14-7.31 (2H, m). Fumarate1106

1H-NMR (DMSO-d6) δ ppm: 0.86-1.00 (1H, m), 1.04-1.47 (4H, m), 1.47-1.57(1H, m), 1.61- 1.70 (1H, m), 1.77-1.87 (1H, m), 2.55-2.72 (2H, m),2.90-3.16 (4H, m), 3.75 (3H, s), 5.25-6.25 (1H, br), 6.35 (1H, d, J =2.9 Hz), 6.96 (1H, dd, J = 1.7, 8.6 Hz), 7.25-7.33 (2H, m), 7.35 (1H, d,J = 8.6 Hz). (2H not found) Oxalate 1107

1H-NMR (CDCl3) δ ppm: 0.96-1.10 (1H, m), 1.10-1.44 (3H, m), 1.48-1.82(5H, m), 2.45- 2.55 (1H, m), 2.55-2.64 (1H, m), 2.98-3.12 (3H, m),3.15-3.25 (1H, m), 3.76 (3H, s), 6.43 (1H, dd, J = 0.8, 3.1 Hz),6.98-7.03 (2H, m), 7.12- 7.15 (1H, m), 7.53 (1H, d, J = 8.5 Hz). — 1108

1H-NMR (DMSO-d6) δ ppm: 0.87-1.02 (1H, m), 1.08-1.50 (4H, m), 1.50-1.60(1H, m), 1.62- 1.72 (1H, m), 1.75-1.86 (1H, m), 2.54-2.76 (2H, m),2.92-3.17 (4H, m), 3.20-5.40 (1H, br), 6.91 (1H, d, J = 1.2 Hz), 7.10(1H, dd, J = 1.9, 8.6 Hz), 7.41 (1H, d, J = 1.9 Hz), 7.52 (1H, d, J =8.6 Hz), 7.97 (1H, d, J = 2.0 Hz). (2H not found) Oxalate

TABLE 134 relative configuration

Example R⁴ NMR Salt 1109

1H-NMR (DMSO-d6) δ ppm: 1.22-1.52 (6H, m), 1.56-1.97 (4H, m), 2.00-2.18(1H, m), 2.75- 2.95 (1H, m), 3.20-3.40 (1H, m), 3.40-3.60 (2H, m),3.96-4.10 (1H, m), 4.20-4.57 (1H, br), 6.91-7.01 (2H, m), 7.19-7.31 (2H,m), 8.69 (1H, brs), 10.11 (1H, brs). 2 Hydrochloride 1110

1H-NMR (CDCl3) δ ppm: 1.15-1.33 (6H, m), 1.48-1.58 (2H, m), 1.66-1.85(4H, m), 2.68 (1H, t, J = 11.8 Hz), 3.02-3.12 (1H, m), 3.23 (1H, dd, J =3.3, 11.4 Hz), 3.29-3.24 (1H, m), 3.76 (1H, td, J = 3.3, 11.4 Hz), 3.88(3H, s), 7.00 (1H, d, J = 2.3 Hz), 7.02-7.30 (2H, m), 7.22-7.29 (1H, m),7.57 (1H, d, J = 8.8 Hz), 7.61 (1H, d, J = 9.0 Hz). — 1111

1H-NMR (DMSO-d6) δ ppm: 1.17-1.36 (2H, m), 1.36-1.51 (4H, m), 1.62-2.00(4H, m), 2.60- 2.17 (1H, m), 2.94-3.05 (1H, m), 3.30-3.50 (1H, m),3.50-3.64 (2H, m), 4.04-4.13 (1H, m), 4.59- 5.50 (1H, br), 7.17 (1H, d,J = 8.9 Hz), 7.31 (1H, d, J = 5.4 Hz), 7.38 (1H, brs), 7.62 (1H, d, J =5.4 Hz), 7.83 (1H, d, J = 8.9 Hz), 8.68 (1H, brs), 10.12 (1H, brs). 2Hydrochloride 1112

1H-NMR (DMSO-d6) δ ppm: 0.99-1.17 (2H, m), 1.30-1.49 (4H, m), 1.55-1.75(2H, m), 1.75-1.98 (2H, m), 1.98-2.13 (1H, m), 3.12- 3.28 (2H, m),3.28-3.50 (1H, m), 3.67-3.85 (2H, m), 6.67 (1H, dd, J = 3.4, 8.6 Hz),7.10 (1H, dd, J = 8.6, 10.7 Hz), 7.28 (1H, dd, J = 2.6, 2.6 Hz), 8.07(1H, d, J = 2.2 Hz), 8.43 (1H, br), 9.94 (1H, br). Hydrochloride 1113

1H-NMR (DMSO-d6) δ ppm: 1.03-1.21 (2H, m), 1.37-1.48 (4H, m), 1.58-1.85(3H, m), 1.95-2.14 (2H, m), 3.23 (1H, d, J = 10.6 Hz), 3.36-3.55 (2H,m), 3.64-3.76 (1H, m), 3.85- 3.96 (1H, m), 7.01 (1H, d, J = 7.6 Hz),7.34 (1H, dd, J = 7.7, 7.7 Hz), 7.46 (1H, d, J = 5.4 Hz), 7.57-7.62 (1H,m), 7.75 (1H, d, J = 5.4 Hz), 8.35-8.6 (1H, m), 9.82 (1H, br).Hydrochloride

TABLE 134 absolute configuration

Example R⁴ NMR Salt 1114

1H-NMR (CDCl3) δ ppm: 0.95-1.10 (4H, m), 1.13 (18H, d, J = 7.3 Hz),1.19-1.47 (7H, m), 1.59-1.67 (1H, m), 1.70-1.84 (3H, m), 2.45- 2.53 (1H,m), 2.57 (1H, dd, J = 10.3, 11.0 Hz), 2.62-2.70 (1H, m), 3.12 (1H, dd, J= 2.7, 11.2 Hz), 3.16-3.24 (1H, m), 7.09 (1H, dd, J = 2.4, 8.9 Hz), 7.17(1H, d, J = 2.4 Hz), 7.27 (1H, dd, J = 2.1, 8.7 Hz), 7.44 (1H, d, J =2.0 Hz), 7.59- 7.65 (2H, m). — 1115

1H-NMR (CDCl3) δ ppm: 0.94-1.12 (4H, m), 1.15-1.46 (4H, m), 1.57-1.68(2H, m), 1.68- 1.85 (11H, m), 2.42-2.51 (1H, m), 2.59-2.70 (2H, m), 3.10(1H, dd, J = 2.7, 11.2 Hz), 3.15- 3.25 (1H, m), 7.29 (1H, dd, J = 2.2,8.6 Hz), 7.30-7.37 (1H, m), 7.42-7.49 (1H, m), 7.76 (1H, d, J = 2.1 Hz),7.93 (1H, d, J = 7.2 Hz), 8.21 (1H, d, J = 8.8 Hz), 8.29 (1H, d, J = 8.3Hz). —

TABLE 135 absolute configuration

Example R⁴ NMR Salt 1116

1H-NMR (DMSO-d6) δ ppm: 0.85-0.99 (4H, m), 1.13-1.35 (3H, m), 1.49-1.75(4H, m), 1.99 (1H, brs), 2.32-2.50 (3H, m), 2.92-3.02 (2H, m), 7.00-7.09(2H, m), 7.19 (1H, dd, J = 2.1, 8.7 Hz), 7.41 (1H, d, J = 1.8 Hz), 7.58(1H, d, J = 8.8 Hz), 7.66 (1H, d, J = 8.8 Hz), 9.56 (1H, brs). — 1117

1H-NMR (DMSO-d6) δ ppm: 1.10-1.57 (7H, m), 1.57-1.71 (2H, m), 1.71-1.82(1H, m), 2.11- 2.22 (1H, m), 3.00-3.40 (6H, m), 7.22 (1H, t, J = 7.4Hz), 7.35-7.85 (4H, m), 8.09 (1H, d, J = 7.8 Hz), 8.37 (1H, brs), 9.96(2H, brs), 11.61 (1H, brs). 2 Hydrochloride

TABLE 136 absolute configuration

Example R⁴ NMR Salt 1118

1H-NMR (CDCl3) δ ppm: 0.98-1.11 (4H, m), 1.17-1.58 (4H, m), 1.58-1.85(4H, m), 2.44- 2.53 (1H, m), 2.56-2.70 (2H, m), 3.12 (1H, dd, J = 2.8,11.2 Hz), 3.15-3.25 (1H, m), 3.90 (3H, s), 7.08-7.16 (2H, m), 7.30 (1H,dd, J = 2.0, 8.7 Hz), 7.46 (1H, d, J = 2.0 Hz), 7.65 (1H, d, J = 4.8Hz), 7.67 (1H, d, J = 4.9 Hz). — 1119

1H-NMR (DMSO-d6) δ ppm: 0.95-1.05 (1H, m), 1.11 (3H, d, J = 6.3 Hz),1.15-1.5 (3H, m), 1.5-1.6 (1H, m), 1.65-1.75 (2H, m), 1.85-1.95 (1H, m),2.65-2.85 (3H, m), 2.85- 4.35 (4H, m), 6.50 (1H, s), 7.33 (1H, dd, J =2.1, 8.7 Hz), 7.4-7.5 (2H, m), 7.57 (1H, d, J = 1.8 Hz), 7.8-7.9 (3H,m). ½ Fumarate 1120

1H-NMR (CDCl3) δ ppm: 0.98-1.12 (4H, m), 1.18-1.48 (4H, m), 1.58-1.69(1H, m), 1.69- 1.85 (3H, m), 2.46-2.54 (1H, m), 2.57 (1H, dd, J = 10.2,11.0 Hz), 2.62-2.70 (1H, m), 3.10- 3.25 (2H, m), 7.22 (1H, dt, J = 2.6,8.8 Hz), 7.35 (1H, dd, J = 1.8, 8.7 Hz), 7.40 (1H, dd, J = 2.5, 9.9 Hz),7.50 (1H, d, J = 1.9 Hz), 7.68-7.77 (2H, m). —

TABLE 137 absolute configuration

Example R⁴ NMR Salt 1121

1H-NMR (CDCl3) δ ppm: 0.97-1.17 (4H, m), 1.17-1.49 (4H, m), 1.53-1.89(4H, m), 2.42- 2.55 (1H, m), 2.55-2.71 (2H, m), 3.08 (1H, dd, J = 2.8,11.3 Hz), 3.13-3.26 (1H, m), 7.19 (1H, dd, J = 2.0, 8.6 Hz), 7.27 (1H,d, J = 5.4 Hz), 7.42 (1H, d, J = 5.4 Hz), 7.58 (1H, d, J = 2.0 Hz), 7.78(1H, d, J = 8.6 Hz). — 1122

1H-NMR (CDCl3) δ ppm: 0.85-1.02 (1H, m), 1.05 (3H, d, J = 6.4 Hz),1.17-1.54 (4H, m), 1.54-1.63 (1H, m), 1.63-1.83 (3H, m), 2.40- 2.55 (1H,m), 2.55-2.65 (1H, m), 2.65-2.74 (1H, m), 3.10 (1H, dd, J = 2.8, 11.4Hz), 3.15-3.26 (1H, m), 7.12 (1H, dd, J = 0.7, 7.6 Hz), 7.30 (1H, t, J =7.8 Hz), 7.35 (1H, d, J = 5.5 Hz), 7.57 (1H, d, J = 5.5 Hz), 7.64 (1H,d, J = 8.0 Hz). — 1123

1H-NMR (DMSO-d6) δ ppm: 0.90-1.04 (1H, m), 1.12 (3H, d, J = 6.4 Hz),1.17-1.35 (2H, m), 1.35-1.49 (1H, m), 1.50-1.62 (2H, m), 1.64- 1.74 (1H,m), 1.84-1.94 (1H, m), 2.65-2.84 (3H, m), 3.10 (1H, dd, J = 2.9, 11.7Hz), 3.21-3.34 (1H, m), 4.30-6.30 (1H, br), 6.49 (2H, s), 7.18 (1H, dd,J = 1.7, 8.4 Hz), 7.39 (1H, d, J = 5.4 Hz), 7.67 (1H, d, J = 5.4 Hz),7.75 (1H, d, J = 1.7 Hz), 7.81 (1H, d, J = 8.4 Hz). Fumarate

TABLE 138 absolute configuration

Example R⁴ NMR Salt 1124

1H-NMR (DMSO-d6) δ ppm at 80° C.: 0.96- 1.38 (6H, m), 1.40-1.50 (1H, m),1.50-1.80 (3H, m), 2.06-2.17 (1H, m), 3.01-3.20 (2H, m), 3.27- 3.40 (2H,m), 3.50-3.65 (1H, m), 5.90-6.39 (1H, br), 7.05-7.22 (2H, m), 7.32 (1H,brs), 8.03 (1H, d, J = 2.0 Hz), 9.64 (1H, brs), 9.81 (1H, brs). 2Hydrochloride 1125

1H-NMR (DMSO-d6) δ ppm: 0.85-1.00 (1H, m), 1.05-1.38 (5H, m), 1.38-1.75(4H, m), 1.87- 2.00 (1H, m), 2.65-3.00 (3H, m), 3.12 (1H, dd, J = 2.8,11.9 Hz), 3.30-3.47 (1H, m), 6.53 (2H, s), 7.04 (1H, d, J = 8.3 Hz),7.14 (1H, brs), 7.37 (1H, d, J = 8.3 Hz), 8.08 (1H, d, J = 2.2 Hz). (3H,not found) Fumarate 1126

1H-NMR (DMSO-d6) δ ppm at 80° C.: 1.02- 1.38 (6H, m), 1.38-1.50 (1H, m),1.50-1.79 (3H, m), 2.05-2.16 (2H, m), 3.10-3.29 (2H, m), 3.29- 3.57 (2H,br), 3.57-3.73 (1H, br), 3.94 (3H, s), 4.30-4.25 (1H, br), 6.91 (1H, d,J = 8.4 Hz), 7.16 (1H, brs), 7.31 (1H, brs), 7.93 (1H, s), 9.72 (1H,brs). 2 Hydrochloride 1127

1H-NMR (DMSO-d6) δ ppm at 80° C.: 1.03- 1.38 (6H, m), 1.40-1.79 (4H, m),2.06-2.18 (1H, m), 2.45 (3H, s), 3.12-3.31 (2H, m), 3.31-3.56 (2H, m),3.56-3.77 (1H, m), 5.39-6.13 (1H, br), 7.08-7.21 (2H, m), 7.21-7.40 (1H,m), 7.95 (1H, d, J = 2.0 Hz), 9.79 (2H, brs). 2 Hydrochloride 1128

1H-NMR (DMSO-d6) δ ppm at 80° C.: 1.02- 1.39 (6H, m), 1.45-1.80 (4H, m),2.08-2.18 (1H, m), 3.10-3.30 (2H, m), 3.32-3.55 (2H, m), 3.55- 3.74 (1H,m), 5.60-6.15 (1H, br), 7.16-7.25 (1H, m), 7.25-7.36 (2H, m), 7.47 (1H,d, J = 8.2 Hz), 7.94 (1H, d, J = 2.0 Hz), 9.55-10.05 (2H, brm). 2Hydrochloride 1129

1H-NMR (DMSO-d6) δ ppm: 0.89-1.03 (1H, m), 1.08-1.35 (5H, m), 1.35-1.60(3H, m), 1.63- 1.73 (1H, m), 1.84-1.96 (1H, m), 2.62-2.85 (3H, m), 3.08(1H, dd, J = 2.8, 11.8 Hz), 3.22-3.35 (1H, m), 6.50 (2H, s), 6.91 (1H,dd, J = 0.9, 2.1 Hz), 7.07 (1H, dd, J = 1.7, 8.3 Hz), 7.36 (1H, s), 7.58(1H, d, J = 8.2 Hz), 7.95 (1H, d, J = 2.2 Hz). (3H not found) Fumarate1130

1H-NMR (DMSO-d6) δ ppm: 1.09-1.55 (7H, m), 1.55-1.80 (3H, m), 2.10-2.22(1H, m), 3.35- 4.13 (5H, m), 4.13-5.22 (1H, br), 7.12 (1H, s), 7.60 (1H,brs), 7.81 (1H, s), 7.98 (1H, brs), 8.15 (1H, s), 10.09 (2H, brs). 2Hydrochloride 1131

1H-NMR (DMSO-d6) δ ppm: 0.90-1.06 (1H, m), 1.15-1.38 (5H, m), 1.47-1.67(3H, m), 1.67- 1.80 (1H, m), 1.99-2.11 (1H, m), 2.80-3.30 (4H, m),3.40-3.60 (1H, m), 4.40-5.10 (1H, br), 7.13- 7.38 (2H, m), 8.15 (1H, d,J = 2.0 Hz), 9.05- 9.58 (1H, br), 9.70-9.95 (1H, br). 2 Hydrochloride

TABLE 139 absolute configuration

Example R⁴ NMR Salt 1132

1H-NMR (CDCl3) δ ppm: 0.94-1.10 (4H, m), 1.13-1.65 (6H, m), 1.65-1.83(2H, m), 2.37- 2.47 (1H, m), 2.55-2.69 (2H, m), 3.05 (1H, dd, J = 2.8,11.2 Hz), 3.12-3.23 (1H, m), 3.77 (3H, s), 6.42 (1H, d, J = 0.7, 3.1Hz), 7.03 (1H, d, J = 3.1 Hz), 7.08 (1H, d, J = 2.0, 8.6 Hz), 7.22- 7.30(1H, m), 7.41 (1H, d, J = 1.8 Hz). — 1133

1H-NMR (DMSO-d6) δ ppm: 0.90-1.05 (1H, m), 1.09-1.35 (5H, m), 1.39-1.60(3H, m), 1.64- 1.76 (1H, m), 1.88-2.00 (1H, m), 2.68-2.79 (1H, m),2.79-2.94 (2H, m), 3.01-3.11 (1H, m), 3.28- 3.40 (1H, m), 3.75 (3H, s),6.36 (1H, d, J = 0.6, 3.1 Hz), 6.51 (2H, s), 6.87 (1H, d, J = 1.7, 8.4Hz), 7.18 (1H, s), 7.27 (1H, d, J = 3.1 Hz), 7.47 (1H, d, J = 8.3 Hz).(3H not found) Fumarate 1134

1H-NMR (CDCl3) δ ppm: 0.82-0.92 (1H, m), 0.94 (3H, d, J = 6.3 Hz),1.06-1.34 (4H, m), 1.38-1.58 (2H, m), 1.59-1.75 (2H, m), 2.28- 2.37 (1H,m), 2.37-2.49 (2H, m), 2.89 (1H, dd, J = 2.6, 10.8 Hz), 2.94-3.04 (1H,m), 3.86 (3H, s), 7.21 (1H, dd, J = 1.9, 8.9 Hz), 7.31 (1H, s), 7.36(1H, d, J = 1.7 Hz), 7.51 (1H, d, J = 8.9 Hz). — 1135

1H-NMR (DMSO-d6) δ ppm: 0.82-0.96 (1H, m), 1.01-1.35 (5H, m), 1.35-1.85(4H, m), 1.85- 1.96 (1H, m), 2.53-3.05 (3H, m), 3.05-3.23 (1H, m),3.23-3.40 (1H, m), 3.76 (3H, s), 6.39-6.57 (3H, m), 6.79 (1H, d, J = 8.0Hz), 7.09 (1H, t, J = 7.8 Hz), 7.17-7.28 (2H, m). (3H not found)Fumarate 1136

1H-NMR (DMSO-d6) δ ppm: 0.93-1.10 (1H, m), 1.10-1.35 (5H, m), 1.41-1.59(3H, m), 1.64- 1.78 (1H, m), 1.91-2.04 (1H, m), 2.75-3.04 (3H, m), 3.11(1H, dd, J = 2.0, 12.0 Hz), 3.32-3.46 (1H, m), 3.85 (3H, s), 6.53 (2H,s), 7.15-7.23 (1H, m), 7.29 (1H, dd, J = 1.9, 8.6 Hz), 7.42- 7.49 (1H,m), 7.53 (1H, d, J = 8.6 Hz), 7.56 (1H, d, J = 8.3 Hz), 7.94 (1H, d, J =1.8 Hz), 8.15 (1H, d, J = 7.7 Hz). (3H not found) Fumarate

TABLE 140 absolute configuration

Example R⁴ NMR Salt 1137

1H-NMR (CDCl3) δ ppm: 0.88-1.08 (4H, m), 1.15-1.57 (4H, m), 1.60-1.68(2H, m), 1.68-1.80 (2H, m), 2.31-2.39 (1H, m), 2.46 (1H, dd, J = 10.4,11.0 Hz), 2.55-2.63 (1H, m), 3.00 (1H, dd, J = 2.8, 11.2 Hz), 3.07-3.18(1H, m), 7.03- 7.09 (2H, m), 7.23-7.29 (2H, m). — 1138

1H-NMR (CDCl3) δ ppm: 0.98-1.10 (4H, m), 1.20-1.46 (4H, m), 1.65-1.90(4H, m), 2.46- 2.67 (3H, m), 3.10-3.25 (2H, m), 6.98 (1H, dd, J = 2.1,8.5 Hz), 7.12 (1H, d, J = 2.1 Hz), 7.54 (1H, d, J = 8.5 Hz). — 1139

1H-NMR (DMSO-d6) δ ppm: 0.89-1.03 (1H, m), 1.11 (3H, d, J = 6.4 Hz),1.17-1.34 (2H, m), 1.34-1.47 (1H, m), 1.51-1.74 (3H, m), 1.82- 1.94 (1H,m), 2.64-2.74 (2H, m), 2.74-2.84 (1H, m), 3.14 (1H, dd, J = 3., 11.9Hz), 3.20-3.33 (1H, m), 6.51 (2H, s), 6.97-7.04 (1H, m), 7.19 (1H, dd, J= 2.4, 11.3 Hz), 7.50 (1H, t, J = 8.7 Hz), 8.90-11.40 (2H, br). (1H notfound) Fumarate 1140

1H-NMR (DMSO-d6) δ ppm: 0.89-1.03 (1H, m), 1.10 (3H, d, J = 6.4 Hz),1.14-1.45 (3H, m), 1.48-1.62 (2H, m), 1.65-1.73 (1H, m), 1.82- 1.92 (1H,m), 2.58-2.81 (3H, m), 3.05 (1H, dd, J = 3.0, 11.7 Hz), 3.19-3.30 (1H,m), 6.51 (2H, s), 7.11-7.18 (1H, m), 7.31-7.41 (2H, m), 9.00- 11.60 (2H,br). (1H not found) Fumarate

TABLE 141 absolute configuration

Example R⁴ NMR Salt 1141

1H-NMR (CDCl3) δ ppm: 0.96-1.10 (4H, m), 1.13 (18H, d, J = 7.3 Hz),1.19-1.50 (7H, m), 1.58-1.67 (1H, m), 1.68-1.84 (3H, m), 2.45- 2.53 (1H,m), 2.57 (1H, dd, J = 10.3, 11.0 Hz), 2.62-2.70 (1H, m), 3.12 (1H, dd, J= 2.7, 11.2 Hz), 3.15-3.24 (1H, m), 7.09 (1H, dd, J = 2.4, 8.9 Hz), 7.17(1H, d, J = 2.4 Hz), 7.27 (1H, dd, J = 2.1, 8.7 Hz), 7.44 (1H, d, J =2.0 Hz), 7.59- 7.65 (2H, m). — 1142

1H-NMR (CDCl3) δ ppm: 0.94-1.12 (4H, m), 1.15-1.46 (4H, m), 1.57-1.68(2H, m), 1.68- 1.85 (11H, m), 2.42-2.51 (1H, m), 2.59-2.70 (2H, m), 3.10(1H, dd, J = 2.7, 11.2 Hz), 3.15- 3.25 (1H, m), 7.29 (1H, dd, J = 2.2,8.6 Hz), 7.30-7.37 (1H, m), 7.42-7.49 (1H, m), 7.76 (1H, d, J = 2.1 Hz),7.93 (1H, d, J = 7.2 Hz), 8.21 (1H, d, J = 8.8 Hz), 8.29 (1H, d, J = 8.3Hz). —

TABLE 142 absolute configuration

Example R⁴ NMR Salt 1143

1H-NMR (DMSO-d6) δ ppm: 0.83-1.00 (4H, m), 1.12-1.35 (3H, m), 1.48-1.75(4H, m), 1.99 (1H, brs), 2.31-2.50 (3H, m), 2.92-3.03 (2H, m), 6.99-7.09(2H, m), 7.19(1H, dd, J = 2.0, 8.7 Hz), 7.41 (1H, d, J = 1.7 Hz), 7.58(1H, d, J = 8.8 Hz), 7.66 (1H, d, J = 8.8 Hz), 9.75 (1H, brs). — 1144

1H-NMR (DMSO-d6) δ ppm: 1.10-1.57 (7H, m), 1.57-1.71 (2H, m), 1.71-1.82(1H, m), 2.11- 2.22 (1H, m), 3.00-3.40 (6H, m), 7.22 (1H, t, J = 7.4Hz), 7.35-7.85 (4H, m), 8.09 (1H, d, J = 7.8 Hz), 8.37 (1H, brs), 9.96(2H, brs), 11.61 (1H, brs). 2 Hydrochloride

TABLE 143 absolute configuration

Example R⁴ NMR Salt 1145

1H-NMR (CDCl3) δ ppm: 0.98-1.12 (4H, m), 1.18-1.58 (4H, m), 1.58-1.85(4H, m), 2.45- 2.53 (1H, m), 2.56-2.70 (2H, m), 3.12 (1H, dd, J = 2.8,11.2 Hz), 3.16-3.25 (1H, m), 3.90 (3H, s), 7.08-7.16 (2H, m), 7.30 (1H,dd, J = 2.01, 8.7 Hz), 7.46 (1H, d, J = 2.0 Hz), 7.65 (1H, d, J = 4.9Hz), 7.67 (1H, d, J = 4.9 Hz). — 1146

1H-NMR (DMSO-d6) δ ppm: 0.92-1.06 (1H, m), 1.11 (3H, d, J = 6.4 Hz),1.16-1.51 (3H, m), 1.52-1.64 (1H, m), 1.64-1.78 (2H, m), 1.82-1.94 (1H,m), 2.65-2.85 (3H, m), 2.85- 4.2 (4H, m), 6.50 (1H, s), 7.33 (1H, dd, J= 2.1, 8.7 Hz), 7.39-7.51 (2H, m), 7.56 (1H, d, J = 1.9 Hz), 7.80-7.89(3H, m). ½ Fumarate 1147

1H-NMR (CDCl3) δ ppm: 0.98-1.12 (4H, m), 1.18-1.48 (4H, m), 1.60-1.69(1H, m), 1.69- 1.85 (3H, m), 2.46-2.54 (1H, m), 2.57 (1H, dd, J = 10.2,11.0 Hz), 2.62-2.71 (1H, m), 3.10- 3.25 (2H, m), 7.22 (1H, dt, J = 2.6,8.8 Hz), 7.35 (1H, dd, J = 1.8, 8.7 Hz), 7.40 (1H, dd, J = 2.5, 9.9 Hz),7.50 (1H, d, J = 1.9 Hz), 7.68-7.77 (2H, m). —

TABLE 144 absolute configuration

Example R⁴ NMR Salt 1148

1H-NMR (CDCl3) δ ppm: 0.97-1.17 (4H, m), 1.17-1.89 (8H, m), 2.41-2.50(1H, m), 2.53- 2.69 (2H, m), 3.08 (1H, dd, J = 2.8, 11.2 Hz), 3.13-3.22(1H, m), 7.18 (1H, dd, J = 2.0, 8.5 Hz), 7.27 (1H, d, J = 5.4 Hz), 7.42(1H, d, J = 5.4 Hz), 7.58 (1H, d, J = 2.0 Hz), 7.78 (1H, d, J = 8.5 Hz).— 1149

1H-NMR (CDCl3) δ ppm: 0.86-1.02 (1H, m), 1.05 (3H, d, J = 6.4 Hz),1.17-1.54 (4H, m), 1.54-1.63 (1H, m), 1.63-1.83 (3H, m), 2.39- 2.55 (1H,m), 2.55-2.65 (1H, m), 2.65-2.74 (1H, m), 3.10 (1H, dd, J = 2.8, 11.4Hz), 3.15-3.26 (1H, m), 7.12 (1H, dd, J = 0.7, 7.6 Hz), 7.30 (1H, t, J =7.8 Hz), 7.35 (1H, d, J = 5.5 Hz), 7.57 (1H, d, J = 5.5 Hz), 7.64 (1H,d, J = 8.0 Hz). — 1150

1H-NMR (DMSO-d6) δ ppm: 0.90-1.04 (1H, m), 1.10-1.35 (5H, m), 1.35-1.62(3H, m), 1.64- 1.74 (1H, m), 1.84-1.95 (1H, m), 2.65-2.84 (3H, m), 3.11(1H, dd, J = 2.8, 11.8 Hz), 3.21-3.35 (1H, m), 6.49 (2H, s), 7.19 (1H,dd, J = 1.8, 8.5 Hz), 7.39 (1H, d, J = 5.4 Hz), 7.68 (1H, d, J = 5.4Hz), 7.75 (1H, d, J = 1.8 Hz), 7.81 (1H, d, J = 8.5 Hz), 7.50-9.40 (1H,br). Fumarate

TABLE 145 absolute configuration

Example R⁴ NMR Salt 1151

1H-NMR (DMSO-d6) δ ppm at 80° C.: 0.96- 1.39 (6H, m), 1.40-1.50 (1H, m),1.50-1.80 (3H, m), 2.05-2.15 (1H, m), 2.98-3.20 (2H, m), 3.20- 3.40 (2H,m), 3.42-3.64 (1H, m), 5.23-6.05 (1H, br), 7.05-7.21 (2H, m), 7.30 (1H,brs), 8.03 (1H, s), 9.56 (1H, brs), 9.77 (1H, brs). 2 Hydrochloride 1152

1H-NMR (DMSO-d6) δ ppm: 0.85-1.00 (1H, m), 1.05-1.38 (5H, m), 1.38-1.75(4H, m), 1.87- 2.00 (1H, m), 2.65-3.00 (3H, m), 3.12 (1H, dd, J = 2.8,11.9 Hz), 3.30-3.47 (1H, m), 6.53 (2H, s), 7.04 (1H, d, J = 8.3 Hz),7.14 (1H, brs), 7.37 (1H, d, J = 8.3 Hz), 8.08 (1H, d, J = 2.2 Hz). (3H,not found) Fumarate 1153

1H-NMR (DMSO-d6) δ ppm at 80° C.: 1.00- 1.38 (6H, m), 1.38-1.50 (1H, m),1.50-1.79 (3H, m), 2.05-2.14 (2H, m), 3.09-3.25 (2H, m), 3.25- 3.50 (2H,br), 3.54-3.70 (1H, br), 3.94 (3H, s), 4.35-5.05 (1H, br), 6.90 (1H, d,J = 8.4 Hz), 7.07-7.20 (1H, m), 7.27 (1H, brs), 7.92 (1H, d, J = 1.8Hz), 9.68 (1H, brs). 2 Hydrochloride 1154

1H-NMR (DMSO-d6) δ ppm at 80° C.: 1.05- 1.38 (6H, m), 1.38-1.52 (1H, m),1.52-1.62 (1H, m), 1.62-1.79 (2H, m), 2.09-2.18 (1H, m), 2.46 (3H, s),3.17-3.37 (2H, m), 3.37-3.66 (2H, m), 3.66-3.75 (1H, m), 6.25-7.10 (1H,br), 7.14 (1H, d, J = 7.8 Hz), 7.19-7.30 (1H, m), 7.40 (1H, brs), 7.97(1H, d, J = 2.1 Hz), 9.88 (2H, brs). 2 Hydrochloride 1155

1H-NMR (DMSO-d6) δ ppm at 80° C.: 1.00- 1.38 (6H, m), 1.45-1.80 (4H, m),2.08-2.18 (1H, m), 3.06-3.27 (2H, m), 3.27-3.49 (2H, m), 3.53- 3.70 (1H,m), 4.94-5.68 (1H, br), 7.13-7.22 (1H, m), 7.25-7.35 (2H, m), 7.45 (1H,d, J = 8.2 Hz), 7.93 (1H, d, J = 1.5 Hz), 9.45-10.00 (2H, brm). 2Hydrochloride 1156

1H-NMR (DMSO-d6) δ ppm: 0.89-1.03 (1H, m), 1.05-1.35 (5H, m), 1.35-1.61(3H, m), 1.61- 1.75 (1H, m), 1.82-1.96 (1H, m), 2.62-2.86 (3H, m), 3.08(1H, d, J = 11.6 Hz), 3.21-3.36 (1H, m), 6.50 (2H, s), 6.91 (1H, d, J =2.0 Hz), 7.07 (1H, dd, J = 1.3, 8.3 Hz), 7.36 (1H, s), 7.58 (1H, d, J =8.2 Hz), 7.95 (1H, d, J = 2.2 Hz). (3H not found) Fumarate 1157

1H-NMR (DMSO-d6) δ ppm: 1.09-1.55 (7H, m), 1.55-1.80 (3H, m), 2.10-2.22(1H, m), 3.30- 4.10 (5H, m), 4.10-5.20 (1H, br), 7.11 (1H, s), 7.58 (1H,brs), 7.80 (1H, s), 7.97 (1H, brs), 8.15 (1H, s), 10.06 (2H, brs). 2Hydrochloride 1158

1H-NMR (DMSO-d6) δ ppm: 0.90-1.10 (1H, m), 1.15-1.38 (5H, m), 1.47-1.69(3H, m), 1.69- 1.80 (1H, m), 2.00-2.11 (1H, m), 2.80-3.40 (4H, m),3.40-3.60 (1H, m), 5.35-6.36 (1H, br), 7.13- 7.44 (2H, m), 8.15 (1H, d,J = 2.0 Hz), 9.08- 9.66 (1H, br), 9.66-10.08 (1H, br). 2 Hydrochloride

TABLE 146 absolute configuration

Example R⁴ NMR Salt 1159

1H-NMR (CDCl3) δ ppm: 0.95-1.10 (4H, m), 1.10-1.54 (4H, m), 1.54-1.65(2H, m), 1.65- 1.83 (2H, m), 2.37-2.47 (1H, m), 2.55-2.69 (2H, m), 3.05(1H, dd, J = 2.8, 11.2 Hz), 3.12-3.23 (1H, m), 3.77 (H, s), 6.42 (1H, d,J = 0.7, 3.1 Hz), 7.03 (1H, d, J = 3.1 Hz), 7.08 (1H, d, J = 2.0, 8.6Hz), 7.22-7.30 (1H, m), 7.41 (1H, d, J = 1.8 Hz). — 1160

1H-NMR (DMSO-d6) δ ppm: 0.90-1.05 (1H, m), 1.09-1.35 (5H, m), 1.39-1.60(3H, m), 1.64- 1.75 (1H, m), 1.88-2.00 (1H, m), 2.67-2.95 (3H, m), 3.07(1H, dd, J = 2.8, 12.0 Hz), 3.28-3.40 (1H, m), 3.75 (3H, s), 6.36 (1H,d, J = 0.6, 3.0 Hz), 6.51 (2H, s), 6.87 (1H, d, J = 1.6, 8.4 Hz), 7.18(1H, s), 7.27 (1H, d, J = 3.0 Hz), 7.47 (1H, d, J = 8.3 Hz). (3H notfound) Fumarate 1161

1H-NMR (CDCl3) δ ppm: 0.82-0.92 (1H, m), 0.94 (3H, d, J = 6.3 Hz),1.06-1.34 (4H, m), 1.38-1.58 (2H, m), 1.59-1.75 (2H, m), 2.28- 2.37 (1H,m), 2.37-2.49 (2H, m), 2.89 (1H, dd, J = 2.6, 10.8 Hz), 2.94-3.04 (1H,m), 3.86 (3H, s), 7.21 (1H, dd, J = 1.9, 8.9 Hz), 7.31 (1H, s), 7.36(1H, d, J = 1.7 Hz), 7.51 (1H, d, J = 8.9 Hz). — 1162

1H-NMR (DMSO-d6) δ ppm: 0.80-0.99 (1H, m), 1.00-1.35 (5H, m), 1.35-1.98(5H, m), 2.53- 3.25 (4H, m), 3.23-3.40 (1H, m), 3.76 (3H, s), 6.40-6.58(3H, m), 3.79 (1H, d, J = 8.0 Hz), 7.09 (1H, t, J = 7.8 Hz), 7.17-7.28(2H, m). (3H not found) Fumarate 1163

1H-NMR (DMSO-d6) δ ppm: 0.93-1.08 (1H, m), 1.10-1.35 (5H, m), 1.401-1.60(3H, m), 1.64-1.75 (1H, m), 1.90-2.03 (1H, m), 2.72- 3.00 (3H, m), 3.11(1H, dd, J = 2.0, 12.0 Hz), 3.32-3.43 (1H, m), 3.85 (3H, s), 6.52 (2H,s), 7.15-7.23 (1H, m), 7.29 (1H, dd, J = 1.9, 8.6 Hz), 7.43-7.49 (1H,m), 7.53 (1H, d, J = 8.6 Hz), 7.56 (1H, d, J = 8.2 Hz), 7.94 (1H, d, J =1.8 Hz), 8.14 (1H, d, J = 7.7 Hz). (3H, not found) Fumarate

TABLE 147 absolute configuration

Example R⁴ NMR Salt 1164

1H-NMR (CDCl3) δ ppm: 0.88-1.08 (4H, m), 1.15-1.42 (3H, m), 1.42-1.60(1H, br), 1.60- 1.69 (2H, m), 1.69-1.82 (H, m), 2.31-2.39 (1H, m), 2.46(1H, dd, J = 10.4, 11.0 Hz), 2.55-2.63 (1H, m), 3.00 (1H, dd, J = 2.8,11.2 Hz), 3.07- 3.18 (1H, m), 7.02-7.09 (2H, m), 7.23-7.29 (2H, m). —1165

1H-NMR (CDCl3) δ ppm: 0.98-1.10 (4H, m), 1.22-1.46 (4H, m), 1.65-1.95(4H, m), 2.46- 2.67 (3H, m), 3.10-3.25 (2H, m), 6.98 (1H, dd, J = 2.1,8.6 Hz), 7.12 (1H, d, J = 2.1 Hz), 7.54 (1H, d, J = 8.6 Hz) — 1166

1H-NMR (DMSO-d6) δ ppm: 0.90-1.03 (1H, m), 1.12 (3H, d, J = 6.4 Hz),1.17-1.34 (2H, m), 1.34-1.48 (1H, m), 1.52-1.74 (3H, m), 1.84- 1.94 (1H,m), 2.65-2.75 (2H, m), 2.74-2.84 (1H, m), 3.14 (1H, dd, J = 3.0, 11.9Hz), 3.22-3.34 (1H, m), 6.51 (2H, s), 6.97-7.04 (1H, m), 7.19 (1H, dd, J= 2.4, 11.3 Hz), 7.51 (1H, t, J = 8.6 Hz), 8.60-11.75 (2H, br). (1H notfound) Fumarate 1167

1H-NMR (DMSO-d6) δ ppm: 0.88-1.02 (1H, m), 1.11 (3H, d, J = 6.4 Hz),1.14-1.45 (3H, m), 1.48-1.62 (2H, m), 1.65-1.73 (1H, m), 1.82- 1.92 (1H,m), 2.60-2.81 (3H, m), 3.05 (1H, dd, J = 3.0, 11.8 Hz), 3.19-3.30 (1H,m), 6.51 (2H, s), 7.11-7.18 (1H, m), 7.30-7.41 (2H, m), 8.85- 11.65 (2H,br). (1H not found) Fumarate

TABLE 148 absolute configuration

Example R⁴ NMR Salt 1168

1H-NMR (DMSO-d6) δ ppm: 0.8-1.0 (4H, m), 1.1-1.6 (7H, m), 1.6-1.7 (1H,m), 1.8-1.9 (1H, m), 2.5-2.75 (3H, m), 2.85-3.9 (5H, m), 6.5-6.55 (2H,m), 7.1-7.2 (2H, m), 7.3- 7.4 (2H, m). Fumarate 1169

1H-NMR (CDCl3) δ ppm: 0.94 (3H, t, J = 7.5 Hz), 0.95-1.1 (1H, m),1.15-1.5 (5H, m), 1.5-1.85 (5H, m), 2.46-2.69 (3H, m), 2.91- 3.01 (1H,m), 3.18 (1H, dd, J = 2.7, 11.2 Hz), 3.91 (3H, s), 7.08-7.14 (2H, m),7.31 (1H, dd, J = 2.1, 8.7 Hz), 7.47 (1H, d, J = 2.0 Hz), 7.64-7.71 (2H,m). — 1170

1H-NMR (DMSO-d6) δ ppm: 0.82-1.03 (4H, m), 1.09-1.36 (2H, m), 1.41-1.59(4H, m), 1.59-1.75 (2H, m), 1.92-2.06 (1H, m), 2.71- 3.07 (3H, m),3.10-3.20 (1H, m), 3.20-3.32 (1H, m), 6.56 (4H, s), 6.97-7.26 (3H, m),11.5 (5H, m). 2 Fumarate 1171

1H-NMR (DMSO-d6) δ ppm: 0.85-1.05 (4H, m), 1.1-1.4 (2H, m), 1.45-1.65(4H, m), 1.65-1.85 (2H, m), 2.05-2.15 (1H, m), 2.85- 3.22 (3H, m),3.22-3.38 (2H, m), 4.09 (1H, br), 7.24 (1H, d, J = 7.5 Hz), 7.35-7.5(2H, m), 7.7-7.8 (2H, m), 9.15-9.35 (1H, m), 9.35-9.55 (1H, m). 2Hydrochloride 1172

1H-NMR (CDCl3) δ ppm: 0.95 (3H, t, J = 7.5 Hz), 0.98-1.09 (1H, m),1.14-1.50 (5H, m), 1.55-1.85 (5H, m), 2.44-2.53 (1H, m), 2.55-2.68 (2H,m), 2.91-3.00 (1H, m), 3.15 (1H, dd, J = 2.7, 11.1 Hz), 7.20 (1H, dd, J= 2.0, 8.6 Hz), 7.27 (1H, dd, J = 0.5, 5.4 Hz), 7.43 (1H, d, J = 5.4Hz), 7.59 (1H, d, J = 2.0 Hz), 7.79 (1H, d, J = 8.6 Hz). — 1173

1H-NMR (DMSO-d6) δ ppm: 0.85-1.05 (4H, m), 1.15-1.35 (2H, m), 1.35-1.5(2H, m), 1.5-1.6 (3H, m), 1.65-1.75 (1H, m), 1.85- 1.95 (1H, m),2.65-2.85 (3H, m), 3.05-3.2 (2H, m), 3.6 (3H, br), 6.51 (2H, s), 7.19(1H, dd, J = 1.9, 8.5 Hz), 7.39 (1H, dd, J = 0.5, 5.4 Hz), 7.68 (1H, d,J = 5.4 Hz), 7.76 (1H, d, J = 1.8 Hz), 7.81 (1H, d, J = 8.5 Hz).Fumarate

TABLE 149 absolute configuration

Example R⁵ R⁶ R⁷ R⁸ R⁹ MS(M + 1) 1174 —H

—H —H —H 327 1175 —H —H

—H —H 317 1176 —H

—H —H —H 327 1177 —H

—H —H —H 314 1178 —H

—H —H —H 328 1179 —H

—H —H —H 310 1180 —H —H

—H —H 344 1181 —H

—H —H —H 357 1182 —H

—H —H —H 344 1183 —H —H

—H —H 328 1184 —H —H

—H —H 342 1185 —H

—H —H —H 323 1186 —H

—H —H —H 328 1187 —H

—H —H —H 330 1188 —H —Cl

—H —H 385 1189 —H —H

—H —H 351 1190 —H

—H —H —H 342 1191 —OCH3 —OCH3 —H —H —H 305 1192 —H —H —O(CH2)2CH3 —H —H303 1193 —H —H

—H —H 343 1194 —F —H —OCH3 —H —H 293 1195 —Cl —H —H —CF3 —H 347 1196 —Cl—H —H —H —H 297 1197 —H

—OCH3 —H —H 381 1198 —OCH3 —H —Cl —H —H 309 1199 —F —Cl —H —H —H 2971200 —CH3 —H —OCH3 —Cl —H 323 1201 —H —OCH3

—H —H 381 1202 —H —H

—H —H 311 1203 —H

—H —H —H 342 1204 —H —H

—H —H 357 1205 —H —H —OCH(CH3)2 —H —H 303 1206 —H

—H —H —H 312 1207 —OCH2CH3 —H —H —H —H 289 1208 —H

—H —H —H 337 1209 —Cl —CF3 —H —H —H 347 1210 —H —H —CH2CH(CH3)2 —H —H301 1211 —CN —H —Cl —H —H 304 1212 —H —H

—H —H 330 1213 —H —H

—H —H 310

TABLE 150 absolute configuration

Example R⁴ MS(M + 1) 1214

296 1215

299 1216

296 1217

301 1218

338 1219

330 1220

303 1221

330 1222

296 1223

314 1224

299 1225

327 1226

316 1227

342 1228

315 1229

299 1230

314 1231

313

TABLE 151 absolute configuration

Example R⁴ MS(M + 1) 1232

277 1233

260 1234

316 1235

329 1236

315 1237

326 1238

322 1239

331 1240

280 1241

264 1242

276 1243

280 1244

246 1245

247 1246

323 1247

296 1248

260 1249

286 1250

302 1251

276 1252

332 1253

297 1254

314 1255

252 1256

261 1257

372 1258

330 1259

373 1260

326 1261

326 1262

277 1263

302 1264

297 1265

264 1266

271 1267

264 1268

246 1269

296 1270

322 1271

247 1272

276 1273

264 1274

247 1275

330 1276

280 1277

261 1278

297 1279

302 1280

266 1281

328 1282

263 1283

266

TABLE 152 absolute configuration

Example R⁴ MS(M + 1) 1284

315 1285

282 1286

245 1287

261 1288

277 1289

312 1290

274 1291

299 1292

281 1293

277 1294

337 1295

317 1296

261 1297

279 1298

267 1299

267 1300

275 1301

297 1302

283 1303

263 1304

249 1305

279 1306

285 1307

279 1308

279 1309

282 1310

275 1311

273 1312

296 1313

297 1314

297 1315

265 1316

259 1317

275 1318

299 1319

319 1320

271 1321

288 1322

277 1323

231 1324

249 1325

271 1326

288 1327

270 1328

309 1329

263 1330

296 1331

311 1332

333 1333

313 1334

328 1335

297 1336

286 1337

313 1338

371 1339

288 1340

323 1341

306

TABLE 153 absolute configuration

Example. R⁴ MS(M + 1) 1342

315 1343

282 1344

245 1345

261 1346

277 1347

312 1348

274 1349

299 1350

333 1351

245 1352

281 1353

299 1354

277 1355

337 1356

317 1357

261 1358

267 1359

267 1360

275 1361

297 1362

283 1363

263 1364

249 1365

279 1366

285 1367

279 1368

279 1369

282 1370

275 1371

273 1372

296 1373

297 1374

297 1375

265 1376

259 1377

275 1378

299 1379

319 1380

271 1381

288 1382

231 1383

249 1384

271 1385

288 1386

270 1387

263 1388

282 1389

337 1390

311 1391

333 1392

313 1393

328 1394

297 1395

286 1396

313 1397

282 1398

371 1399

288 1400

323 1401

306

TABLE 154 absolute configuration

Example. R⁴ MS(M + 1) 1402

307 1403

325 1404

309 1405

316 1406

309 1407

296 1408

321 1409

297 1410

341 1411

357 1412

331 1413

347 1414

331 1415

311 1416

333 1417

325 1418

335 1419

347 1420

297 1421

321 1422

314 1423

323 1424

332 1425

315 1426

331

TABLE 155 absolute configuration

Example. R⁴ MS(M + 1) 1427

307 1428

325 1429

309 1430

316 1431

309 1432

296 1433

321 1434

297 1435

341 1436

357 1437

331 1438

347 1439

331 1440

311 1441

333 1442

325 1443

335 1444

347 1445

297 1446

321 1447

314 1448

323 1449

332 1450

315 1451

331

TABLE 156 absolute configuration

Example. R⁴ MS(M + 1) 1452

307 1453

325 1454

309 1455

316 1456

313 1457

309 1458

296 1459

321 1460

297 1461

341 1462

357 1463

331 1464

347 1465

331 1466

327 1467

311 1468

333 1469

325 1470

335 1471

347 1472

321 1473

314 1474

323 1475

332 1476

315 1477

331

TABLE 157 absolute configuration

Example. R⁴ MS(M + 1) 1478

307 1479

325 1480

309 1481

316 1482

313 1483

309 1484

296 1485

321 1486

297 1487

341 1488

357 1489

331 1490

347 1491

331 1492

327 1493

311 1494

333 1495

325 1496

335 1497

347 1498

321 1499

314 1500

323 1501

332 1502

315 1503

331

TABLE 158 relative configuration

Example. R⁴ MS(M + 1) 1504

281 1505

299 1506

283 1507

290 1508

283 1509

270 1510

295 1511

271 1512

315 1513

331 1514

305 1515

321 1516

305 1517

301 1518

285 1519

307 1520

299 1521

309 1522

321 1523

271 1524

295 1525

288 1526

297 1527

306 1528

289 1529

305

TABLE 159 absolute configuration

Example. R⁴ MS(M + 1) 1530

299 1531

270 1532

295 1533

271 1534

315 1535

331 1536

305 1537

321 1538

321 1539

295 1540

288 1541

306 1542

289 1543

305

TABLE 160 absolute configuration

Example. R⁴ MS(M + 1) 1544

281 1545

299 1546

270 1547

295 1548

271 1549

315 1550

331 1551

305 1552

321 1553

305 1554

321 1555

295 1556

288 1557

306 1558

289 1559

305

TABLE 161 relative configuration

Example. R⁴ MS(M + 1) 1560

275 1561

291

TABLE 162 absolute configuration

Example. R⁴ MS(M + 1) 1562

267 1563

285 1564

269 1565

276 1566

251 1567

273 1568

269 1569

256 1570

281 1571

257 1572

301 1573

317 1574

275 1575

291 1576

307 1577

291 1578

271 1579

293 1580

285 1581

295 1582

307 1583

257 1584

281 1585

274 1586

283 1587

292

TABLE 163 absolute configuration

Example. R⁴ MS(M + 1) 1588

267 1589

285 1590

269 1591

276 1592

251 1593

273 1594

269 1595

256 1596

281 1597

257 1598

301 1599

317 1600

275 1601

291 1602

307 1603

291 1604

271 1605

293 1606

285 1607

295 1608

307 1609

257 1610

281 1611

274 1612

283 1613

292

TABLE 164 absolute configuration

Example. R⁴ MS(M + 1) 1614

285 1615

269 1616

276 1617

269 1618

281 1619

257 1620

301 1621

317 1622

291 1623

307 1624

287 1625

271 1626

293 1627

295 1628

307 1629

257 1630

281 1631

274 1632

292 1633

275 1634

291

TABLE 165 absolute configuration

Example. R⁴ MS(M + 1) 1635

285 1636

269 1637

276 1638

269 1639

281 1640

257 1641

301 1642

317 1643

291 1644

307 1645

287 1646

271 1647

293 1648

295 1649

307 1650

257 1651

281 1652

274 1653

283 1654

292 1655

275 1656

291

Pharmacological Study 1

Measurement of Serotonin (5-HT) Uptake Inhibitory Activity of TestCompound Using Rat Brain Synaptosome

Male Wistar rats were decapitated, and their brains were removed anddissected to remove the frontal cortex. The separated frontal cortex wasplaced in a 20-fold weight of a 0.32 molarity (M) sucrose solution andhomogenized with a potter homogenizer. The homogenate was centrifuged at1000 g at 4° C. for 10 minutes, and the supernatant was furthercentrifuged at 20000 g at 4° C. for 20 minutes. The pellet was suspendedin an incubation buffer (20 mM HEPES buffer (pH 7.4) containing 10 mMglucose, 145 mM sodium chloride, 4.5 mM potassium chloride, 1.2 mMmagnesium chloride, and 1.5 mM calcium chloride). The suspension wasused as a crude synaptosome fraction.

Uptake reaction was performed using each well of a 96-well round-bottomplate and a 200 μl volume in total of a solution containing pargyline(final concentration: 10 μM) and ascorbic acid (final concentration: 0.2mg/ml).

Specifically, a solvent, unlabeled 5-HT, and serially diluted testcompounds were separately added to the wells, and the synaptosomefraction was added in an amount 1/10 of the final volume to each welland preincubated at 37° C. for 10 minutes. Then, a tritium-labeled 5-HTsolution (final concentration: 8 μM) was added thereto to initiateuptake reaction at 37° C. 10 minutes later, the uptake reaction wasterminated by suction filtration through a 96-well glass fiber filterplate. Furthermore, the filter was washed with a cold saline and thensufficiently dried. MicroScint-O (PerkinElmer Co., Ltd.) was addedthereto, and the residual radioactivity on the filter was measured.

An uptake value obtained by the addition of only the solvent was definedas 100%, and an uptake value (nonspecific uptake value) obtained by theaddition of the unlabeled 5-HT (final concentration: 10 μM) was definedas 0%. A 50% inhibitory concentration was calculated from the testcompound concentrations and inhibitory activities thereat. The resultsare shown in Table 60.

TABLE 60 50% Inhibitory concentration Test Compound (nM) Compound ofExample 2 7.1 Compound of Example 7 1.0 Compound of Example 8 2.4Compound of Example 10 6.2 Compound of Example 13 5.1 Compound ofExample 15 12.5 Compound of Example 27 5.8 Compound of Example 33 2.6Compound of Example 72 2.6 Compound of Example 77 0.8 Compound ofExample 85 7.2 Compound of Example 106 9.7 Compound of Example 112 7.1Compound of Example 118 13.7 Compound of Example 120 9.2 Compound ofExample 124 8.5 Compound of Example 125 4.7 Compound of Example 130 5.3Compound of Example 131 6.1 Compound of Example 132 8.8 Compound ofExample 136 1.3 Compound of Example 150 5.4 Compound of Example 165 2.0Compound of Example 186 5.2 Compound of Example 187 5.8 Compound ofExample 188 6.0 Compound of Example 191 3.2 Compound of Example 192 2.9Compound of Example 193 3.4 Compound of Example 196 4.4 Compound ofExample 233 7.4 Compound of Example 246 6.8 Compound of Example 247 42.8Compound of Example 273 44.0 Compound of Example 276 7.2 Compound ofExample 281 5.8 Compound of Example 285 19.7 Compound of Example 28856.1 Compound of Example 300 89.1 Compound of Example 307 19.3 Compoundof Example 322 9.6 Compound of Example 344 6.8 Compound of Example 34610.0 Compound of Example 348 6.4 Compound of Example 405 6.4 Compound ofExample 409 35.6 Compound of Example 468 3.8 Compound of Example 577 5.2Compound of Example 579 4.5 Compound of Example 580 2.5 Compound ofExample 582 4.1 Compound of Example 586 5.2 Compound of Example 587 0.9Compound of Example 593 4.9 Compound of Example 610 4.6 Compound ofExample 621 7.0 Compound of Example 641 2.2 Compound of Example 654 1.5Compound of Example 717 4.2 Compound of Example 778 87.5 Compound ofExample 780 6.5 Compound of Example 781 6.2 Compound of Example 791 1.4Compound of Example 717 42.6 Compound of Example 805 28.1 Compound ofExample 841 7.3 Compound of Example 867 4.7 Compound of Example 884 7.3Compound of Example 895 5.4 Compound of Example 918 10.0 Compound ofExample 962 18.7 Compound of Example 983 6.5 Compound of Example 993 4.8Compound of Example 1026 2.4 Compound of Example 1047 0.7 Compound ofExample 1083 5.1 Compound of Example 1113 5.4 Compound of Example 11218.5 Compound of Example 1124 7.1 Compound of Example 1318 40.7 Compoundof Example 1326 37.8 Compound of Example 1333 84.2 Compound of Example1341 6.8 Compound of Example 1534 38.1

Pharmacological Study 2

Measurement of Norepinephrine (NE) Uptake Inhibitory Activity of TestCompound Using Rat Brain Synaptosome

Male Wistar rats were decapitated, and their brains were removed anddissected to remove the hippocampus. The separated hippocampus wasplaced in a 20-fold weight of a 0.32 molarity (M) sucrose solution andhomogenized with a potter homogenizer. The homogenate was centrifuged at1000 g at 4° C. for 10 minutes, and the supernatant was furthercentrifuged at 20000 g at 4° C. for 20 minutes. The pellet was suspendedin an incubation buffer (20 mM HEPES buffer (pH 7.4) containing 10 mMglucose, 145 mM sodium chloride, 4.5 mM potassium chloride, 1.2 mMmagnesium chloride, and 1.5 mM calcium chloride). The suspension wasused as a crude synaptosome fraction.

Uptake reaction was performed using each well of a 96-well round-bottomplate and a 200 μl volume in total of a solution containing pargyline(final concentration: 10 μM) and ascorbic acid (final concentration: 0.2mg/ml).

Specifically, a solvent, unlabeled NE, and serially diluted testcompounds were separately added to the wells, and the synaptosomefraction was added in an amount 1/10 of the final volume to each welland preincubated at 37° C. for 10 minutes. Then, a tritium-labeled NEsolution (final concentration: 12 nM) was added thereto to initiateuptake reaction at 37° C. Ten minutes later, the uptake reaction wasterminated by suction filtration through a 96-well glass fiber filterplate. Furthermore, the filter was washed with a cold saline and thensufficiently dried. MicroScint-O (PerkinElmer Co., Ltd.) was addedthereto, and the residual radioactivity on the filter was measured.

An uptake value obtained by the addition of only the solvent was definedas 100%, and an uptake value (nonspecific uptake value) obtained by theaddition of the unlabeled NE (final concentration: 10 μM) was defined as0%. A 50% inhibitory concentration was calculated from the test compoundconcentrations and inhibitory activities thereat. The results are shownin Table 61.

TABLE 61 50% Inhibitory concentration Test Compound (nM) Compound ofExample 2 4.6 Compound of Example 7 9.5 Compound of Example 8 60.9Compound of Example 10 8.8 Compound of Example 13 14.3 Compound ofExample 15 11.0 Compound of Example 27 0.9 Compound of Example 33 0.7Compound of Example 72 1.0 Compound of Example 77 3.9 Compound ofExample 85 4.9 Compound of Example 106 37.2 Compound of Example 112 87.3Compound of Example 118 3.7 Compound of Example 120 9.2 Compound ofExample 124 0.8 Compound of Example 125 1.9 Compound of Example 130 0.5Compound of Example 131 0.7 Compound of Example 132 3.1 Compound ofExample 136 0.5 Compound of Example 150 23.6 Compound of Example 165 2.4Compound of Example 186 3.8 Compound of Example 187 6.0 Compound ofExample 188 0.8 Compound of Example 191 2.1 Compound of Example 192 3.6Compound of Example 193 4.4 Compound of Example 196 1.7 Compound ofExample 233 3.2 Compound of Example 246 3.8 Compound of Example 247 6.6Compound of Example 273 6.8 Compound of Example 276 4.5 Compound ofExample 281 2.0 Compound of Example 285 1.4 Compound of Example 288 22.0Compound of Example 300 9.9 Compound of Example 307 40.4 Compound ofExample 322 40.1 Compound of Example 344 7.5 Compound of Example 346 8.8Compound of Example 348 4.6 Compound of Example 405 4.4 Compound ofExample 409 9.1 Compound of Example 468 7.5 Compound of Example 577 5.9Compound of Example 579 5.1 Compound of Example 580 5.4 Compound ofExample 582 6.0 Compound of Example 586 4.0 Compound of Example 587 1.9Compound of Example 593 3.3 Compound of Example 610 5.9 Compound ofExample 621 0.7 Compound of Example 641 76.0 Compound of Example 654 1.0Compound of Example 717 4.8 Compound of Example 778 4.2 Compound ofExample 780 0.6 Compound of Example 781 3.0 Compound of Example 791 0.7Compound of Example 717 30.4 Compound of Example 805 0.9 Compound ofExample 841 1.0 Compound of Example 867 11.7 Compound of Example 884 4.8Compound of Example 895 3.0 Compound of Example 918 0.8 Compound ofExample 962 31.9 Compound of Example 983 47.6 Compound of Example 9938.7 Compound of Example 1026 4.2 Compound of Example 1047 0.7 Compoundof Example 1083 2.5 Compound of Example 1113 1.7 Compound of Example1121 0.7 Compound of Example 1124 0.8 Compound of Example 1318 6.6Compound of Example 1326 1.8 Compound of Example 1333 39.6 Compound ofExample 1341 42.7 Compound of Example 1534 4.0

Pharmacological Study 3

Measurement of Dopamine (DA) Uptake Inhibitory Activity of Test CompoundUsing Rat Brain Synaptosome

Male Wistar rats were decapitated, and their brains were removed anddissected to remove the corpus striatum. The separated corpus striatumwas placed in a 20-fold weight of a 0.32 molarity (M) sucrose solutionand homogenized with a potter homogenizer. The homogenate wascentrifuged at 1000 g at 4° C. for 10 minutes, and the supernatant wasfurther centrifuged at 20000 g at 4° C. for 20 minutes. The pellet wassuspended in an incubation buffer (20 mM HEPES buffer (pH 7.4)containing 10 mM glucose, 145 mM sodium chloride, 4.5 mM potassiumchloride, 1.2 mM magnesium chloride, and 1.5 mM calcium chloride). Thesuspension was used as a crude synaptosome fraction.

Uptake reaction was performed using each well of a 96-well round-bottomplate and a 200 μl volume in total of a solution containing pargyline(final concentration: 10 μM) and ascorbic acid (final concentration: 0.2mg/ml).

Specifically, a solvent, unlabeled DA, and serially diluted testcompounds were separately added to the wells, and the synaptosomefraction was added in an amount 1/10 of the final volume to each welland preincubated at 37° C. for 10 minutes. Then, a tritium-labeled DAsolution (final concentration: 2 nM) was added thereto to initiateuptake reaction at 37° C. Ten minutes later, the uptake reaction wasterminated by suction filtration through a 96-well glass fiber filterplate. Furthermore, the filter was washed with a cold saline and thensufficiently dried. MicroScint-O (PerkinElmer Co., Ltd.) was addedthereto, and the residual radioactivity on the filter was measured.

An uptake value obtained by the addition of only the solvent was definedas 100%, and an uptake value (nonspecific uptake value) obtained by theaddition of the unlabeled DA (final concentration: 10 μM) was defined as0%. A 50% inhibitory concentration was calculated from the test compoundconcentrations and inhibitory activities thereat. The results are shownin Table 62.

TABLE 62 50% Inhibitory concentration Test Compound (nM) Compound ofExample 2 85.9 Compound of Example 7 78.9 Compound of Example 8 377.8Compound of Example 10 64.8 Compound of Example 13 85.4 Compound ofExample 15 68.4 Compound of Example 27 31.9 Compound of Example 33 15.1Compound of Example 72 47.9 Compound of Example 77 41.2 Compound ofExample 85 95.7 Compound of Example 106 336.8 Compound of Example 112263.7 Compound of Example 118 8.3 Compound of Example 120 187.2 Compoundof Example 124 9.1 Compound of Example 125 5.2 Compound of Example 1303.9 Compound of Example 131 8.3 Compound of Example 132 3.9 Compound ofExample 136 7.7 Compound of Example 150 200.5 Compound of Example 1656.8 Compound of Example 186 29.8 Compound of Example 187 12.1 Compoundof Example 188 7.9 Compound of Example 191 13.5 Compound of Example 1928.6 Compound of Example 193 5.7 Compound of Example 196 18.3 Compound ofExample 233 38.8 Compound of Example 246 8.8 Compound of Example 247 8.7Compound of Example 273 8.7 Compound of Example 276 10.9 Compound ofExample 281 6.6 Compound of Example 285 43.9 Compound of Example 28874.7 Compound of Example 300 81.3 Compound of Example 307 68.2 Compoundof Example 322 67.7 Compound of Example 344 9.8 Compound of Example 3467.8 Compound of Example 348 27.3 Compound of Example 405 74.8 Compoundof Example 409 165.3 Compound of Example 468 54.0 Compound of Example577 47.9 Compound of Example 579 46.5 Compound of Example 580 202.0Compound of Example 582 68.8 Compound of Example 586 93.0 Compound ofExample 587 76.1 Compound of Example 593 9.7 Compound of Example 61013.2 Compound of Example 621 128.5 Compound of Example 641 9.7 Compoundof Example 654 9.0 Compound of Example 717 60.1 Compound of Example 7784.9 Compound of Example 780 4.3 Compound of Example 781 5.2 Compound ofExample 791 160.9 Compound of Example 717 83.8 Compound of Example 8055.1 Compound of Example 841 7.0 Compound of Example 867 85.7 Compound ofExample 884 52.8 Compound of Example 895 19.9 Compound of Example 91842.0 Compound of Example 962 69.5 Compound of Example 983 172.6 Compoundof Example 993 39.6 Compound of Example 1026 12.3 Compound of Example1047 1.1 Compound of Example 1083 53.7 Compound of Example 1113 26.0Compound of Example 1121 29.9 Compound of Example 1124 49.3 Compound ofExample 1318 83.5 Compound of Example 1326 91.8 Compound of Example 133373.0 Compound of Example 1341 113.3 Compound of Example 1534 214.8

Pharmacological Study 4

Forced Swimming Test

This test was conducted according to the method of Porsolt et al.(Porsolt, R. D., et al., Behavioural despair in mice: A primaryscreening test for antidepressants. Arch int Pharmacodyn. Ther., 229, pp327-336 (1977)).

A test compound was suspended in a 5% gum arabic/saline (w/v), and thissuspension was orally administered to male ICR mice (CLEA Japan, Inc.(JCL), 5 to 6 week old). One hour later, the mice were placed in a watertank having a water depth of 9.5 cm and a water temperature of 21 to 25°C. and immediately thereafter allowed to try to swim for 6 minutes.Then, a time during which the mouse was immobile (immobility time) wasmeasured for the last 4 minutes. A SCANET MV-20 AQ system manufacturedby Melquest Ltd. was used in the measurement and analysis of theimmobility time.

In this experiment, the animals treated with the test compoundsexhibited a reduction in immobility time. This demonstrates that thetest compounds are useful as antidepressants.

The invention claimed is:
 1. A method for treating depression and/ordepression status caused by adjustment disorder, comprisingadministering to a subject in need a compound represented by the formula(1) or a pharmaceutically acceptable salt thereof:

wherein m=2, l=1 and n=1; X represents CH₂—; R¹ represents hydrogen, aC1-C6 alkyl group, a hydroxy C1-C6 alkyl group, a protecting groupselected from unsubstituted C1-C6 alkanoyl, phthaloyl, C1-C6alkoxycarbonyl, unsubstituted aralkyloxycarbonyl,9-fluorenylmethoxycarbonyl, nitrophenylsulfenyl, aralkyl and C1-C6alkylsilyl groups, or a tri C1-C6 alkylsilyloxy C1-C6 alkyl group; R²and R³, which are the same or different, each independently representhydrogen or a C1-C6 alkyl group; or R₂ and R₃ are bonded to form acyclo-C3-C8 alkyl group; and R⁴ represents any of (1) a phenyl group,(2) an indolyl group, (3) a benzothienyl group, (4) a naphthyl group,(5) a benzofuryl group, (6) a quinolyl group, (7) an isoquinolyl group,(8) a pyridyl group, (9) a thienyl group, (10) a dihydrobenzoxazinylgroup, (11) a dihydrobenzodioxinyl group, (12) a dihydroquinolyl group,(13) a chromanyl group, (14) a quinoxalinyl group, (15) a dihydroindenylgroup, (16) a dihydrobenzofutyl group, (17) a benzodioxolyl group, (18)an indazolyl group, (19) a benzothiazolyl group, (20) an indolinylgroup, (21) a thienopyridyl group, (22) a tetrahydrobenzazepinyl group,(23) a tetrahydrobenzodiazepinyl group, (24) a dihydrobenzodioxepinylgroup, (25) a fluorenyl group, (26) a pyridazinyl group, (27) atetrahydroquinolyl group, (28) a carbazolyl group, (29) a phenanthrylgroup, (30) a dihydroacenaphthylenyl group, (31) a pyrrolopyridyl group,(32) an anthryl group, (33) a benzodioxinyl group, (34) a pyrrolidinylgroup, (35) a pyrazolyl group, (36) an oxadiazolyl group, (38) atetrahydronaphthyl group, (39) a dihydroquinazolinyl group, (40) abenzoxazolyl group, (41) a thiazolyl group, (42) a quinazolinyl group,(43) a phthalazinyl group, (44) a pyrazinyl group, and (45) a chromenylgroup, wherein these aromatic or heterocyclic groups may have one ormore substituent(s) selected from (1-1) a halogen atom, (1-2) a C1-C6alkyl group, (1-3) a C1-C6 alkanoyl group, (1-4) a halogen-substitutedC1-C6 alkyl group, (1-5) a halogen-substituted C1-C6 alkoxy group, (1-6)a cyano group, (1-7) a C1-C6 alkoxy group, (1-8) a C1-C6 alkyithiogroup, (1-9) an imidazolyl group, (1-10) a tri C1-C6 alkylsilyl group,(1-11) an oxadiazolyl group which may have one or more C1-C6 alkylgroup(s), (1-12) a pyrrolidinyl group which may have one or more oxogroup(s), (1-13) a phenyl group which may have one or more C1-C6 alkoxygroup(s), (1-14) a C1-C6 alkylamino C1-C6 alkyl group, (1-15) an oxogroup, (1-16) a pyrazolyl group which may have one or more C1-C6 alkylgroup(s), (1-17) a thienyl group, (1-18) a furyl group, (1-19) athiazolyl group which may have one or more C1-C6 alkyl group(s), (1-20)a C1-C6 alkylamino group, (1-21) a pyrimidyl group which may have one ormore C1-C6 alkyl group(s), (1-22) a phenyl C2-C6 alkenyl group, (1-23) aphenoxy group which may have one or more halogen atom(s), (1-24) aphenoxy C1-C6 alkyl group, (1-25) a pyrralidinyl C1-C6 alkoxy group,(1-26) a C1-C6 alkylsulfamoyl group, (1-27) a pyridazinyloxy group whichmay have one or more C1-C6 alkyl group(s), (1-28) a phenyl C1-C6 alkylgroup, (1-29) a C1-C6 alkylamino C1-C6 alkoxy group, (1-30) animidazolyl C1-C6 alkyl group, (1-31) a phenyl C1-C6 alkoxy group, (1-32)a hydroxy group, (1-33) a C1-C6 alkoxycarbonyl group, (1-34) a hydroxylC1-C6 alkyl group, (1-35) an oxazolyl group, (1-36) a piperidyl group,(1-37) a pyrrolyl group, (1-38) a morpholinyl C1-C6 alkyl group, (1-39)a piperazinyl C1-C6 alkyl group which may have one or more C1-C6 alkylgroup(s), (1-40) a piperidyl C1-C6 alkyl group, (1-41) a pyrrolidinylC1-C6 alkyl group, (1-42) a morpholinyl group, and (1-43) a piperazinylgroup which may have one or more C1-C6 alkyl group(s).
 2. The methodaccording to claim 1, wherein in the compound represented by the formula(1) or a pharmaceutically acceptable salt thereof R⁴ represents any of(1) a phenyl group, (2) an indolyl group, (3) a benzothienyl group, (4)a naphthyl group, (5) a benzofuryl group, (6) a quinolyl group, (7) anisoquinolyl group, (8) a pyridyl group, (9) a thienyl group, (10) adihydrobenzoxazinyl group, (11) a dihydrobenzodioxinyl group, (12) adihydroquinolyl group, (13) a chromanyl group, (14) a quinoxallnylgroup, (15) a dihydroindenyl group, (16) a dihydrobenzofuryl group, (17)a benzodioxolyl group, (18) an indazolyl group, (19) a benzothiazolylgroup, (20) an indolinyl group, (21) a thienopyridyl group, (22) atetrahydrobenzazepinyl group, (23) a tetrahydrobenzodiazepinyl group,(24) a dihydrobenzadioxepinyl group, (25) a fluorenyl group, (26) apyridazinyl group, (27) a tetrahydroquinolyl group, (28) a carbazolylgroup, (29) a phenanthryl group, (30) a dihydroacenaphthylenyl group,(31) a pyrrolopyridyl group, (32) an anthryl group, (33) a benzadioxinylgroup, (34) a pyrrolidinyl group, (35) a pyrazolyl group, (36) anoxadiazolyl group, (38) a tetrahydronaphthyl group, (39) adihydroquinazolinyl group, (40) a benzoxazolyl group, (41) a thiazolylgroup, (42) a quinazolinyl group, (43) a phthalazinyl group, (44) apyrazinyl group, and (45) a chromenyl group, wherein these aromatic orheterocyclic groups may have 1 to 4 substituent(s) selected from (1-1) ahalogen atom, (1-2) a C1-C6 alkyl group, (1-3) a C1-C6 alkanoyl group,(1-4) a halogen-substituted C1-C6 alkyl group, (1-5) ahalogen-substituted C1-C6 alkoxy g oup, (1-6) a cyano group, (1-7) aC1-C6 alkoxy group, (1-8) a C1-C6 alkylthio group, (1-9) an imidazolylgroup, (1-10) a tri C1-C6 alkylsilyl group, (1-11) an oxadiazolyl groupwhich may have 1 C1-C6 alkyl group, (1-12) a pyrrolidinyl group whichmay have 1 oxo group, (1-13) a phenyl group which may have 1 C1-C6alkoxy group, (1-14) a C1-C6 alkylamino C1-C6 alkyl group, (1-15) an oxogroup, (1-16) a pyrazolyl group which may have 1 C1-C6 alkyl group,(1-17) a thienyl group, (1-18) a furyl group, (1-19) a thiazolyl groupwhich may have 1 C1-C6 alkyl group, (1-20) a C1-C6 alkylamino group,(1-21) a pyrimidyl group which may have 1 C1-C6 alkyl group, (1-22) aphenyl C2-C6 alkenyl group, (1-23) a phenoxy group which may have 1halogen atom, (1-24) a phenoxy C1-C6 alkyl group, (1-25) a pyrrolidinylC1-C6 alkoxy group, (1-26) a C1-C6 alkylsulfamoyl group, (1-27) apyridazinyloxy group which may have 1 C1-C6 alkyl group, (1-28) a phenylC1-C6 alkyl group, (1-29) a C1-C6 alkylamino C1-C6 alkoxy group, (1-30)an imidazolyl C1-C6 alkyl group, (1-31) a phenyl C1-C6 alkoxy group,(1-32) a hydroxy group, (1-33) a C1-C6 alkoxycarbonyl group, (1-34) ahydroxy C1-C6 alkyl group, (1-35) an oxazolyl group, (1-36) a piperidylgroup, (1-37) a pyrrolyl group, (1-38) a morpholinyl C1-C6 alkyl group,(1-39) a piperazinyl C1-C6 alkyl group which may have 1 C1-C6 alkylgroup, (1-40) a piperidyl C1-C6 alkyl group, (1-41) a pyrrolidinyl C1-C6alkyl group, (1-42) a morpholinyl group, and (1-43) a piperazinyl groupwhich may have 1 C1-C6 alkyl group.
 3. The method according to claim 2,wherein in the compound represented by the formula (1) or apharmaceutically acceptable salt thereof m represents 2; l and nrespectively represent 1; X represents —CH₂—; R¹ represents hydrogen, aC1-C6 alkyl group, a hydroxy C1-C6 alkyl group, a benzyl group, or a triC1-C6 alkylsilyloxy C1-C6 alkyl group; and R⁴ represents any of (1) aphenyl group, (2) an indolyl group, (4) a naphthyl group, (5) abenzofuryl group, and (31) a pyrrolopyridyl group, wherein thesearomatic or heterocyclic groups may have 1 to 4 substituent(s) selectedfrom (1-1) a halogen atom, (1-2) a C1-C6 alkyl group, (1-3) a C1-C6alkanoyl group, (1-4) a halogen-substituted C1-C6 alkyl group, (1-5) ahalogen-substituted C1-C6 alkoxy group, (1-6) a cyano group, (1-7) aC1-C6 alkoxy group, (1-8) a C1-C6 alkylthio group, (1-9) an imidazolylgroup, (1-10) a tri C1-C6 alkylsilyl group, (1-11) an oxadiazolyl groupwhich may have 1 C1-C6 alkyl group, (1-12) a pyrrolidinyl group whichmay have 1 oxo group, (1-13) a phenyl group which may have 1 C1-C6alkoxy group, (1-14) a C1-C6 alkylamino C1-C6 alkyl group, (1-15) an oxogroup, (1-16) a pyrazolyl group which may have 1 C1-C6 alkyl group,(1-17) a thienyl group, (1-18) a furyl group, (1-19) a thiazolyl groupwhich may have 1 C1-C6 alkyl group, (1-20) a C1-C6 alkylamino group,(1-21) a pyrimidyl group which may have 1 C1-C6 alkyl group, (1-22) aphenyl C2-C6 alkenyl group, (1-23) a phenoxy group which may have 1halogen atom, (1-24) a phenoxy C1-C6 alkyl group, (1-25) a pyrrolidinylC1-C6 alkoxy group, (1-26) a C1-C6 alkylsulfamoyl group, (1-27) apyridazinyloxy group which may have 1 C1-C6 alkyl group, (1-28) a phenylC1-C6 alkyl group, (1-29) a C1-C6 alkylamino C1-C6 alkoxy group, (1-30)an imidazolyl C1-C6 alkyl group, (1-31) a phenyl C1-C6 alkoxy group,(1-32) a hydroxy group, (1-34) a hydroxy C1-C6 alkyl group, (1-35) anoxazolyl group, (1-36) a piperidyl group, (1-37) a pyrrolyl group,(1-38) a morpholinyl C1-C6 alkyl group, (1-39) a piperazinyl C1-C6 alkylgroup which may have 1 C1-C6 alkyl group(s), (1-40) a piperidyl C1-C6alkyl group, (1-41) a pyrrolidinyl C1-C6 alkyl group, (1-42) amorpholinyl group, and (1-43) a piperazinyl group which may have 1 C1-C6alkyl group.
 4. The method according to claim 3, wherein in the compoundrepresented by the formula (1) or a pharmaceutically acceptable saltthereof R¹ represents hydrogen; R² and R³, which are the same ordifferent, each independently represent a C1-C6 alkyl group; or R² andR³ are bonded to form a cyclo-C3-C8 alkyl group; and R⁴ represents anyof (1) a phenyl group, (2) an indolyl group, (4) a naphthyl group, (5) abenzofuryl group, and (31) a pyrrolopyridyl group, wherein thesearomatic or heterocyclic groups may have 1 to 2 substituent(s) selectedfrom (1-1) a halogen atom, (1-2) a C1-C6 alkyl group, (1-5) ahalogen-substituted C1-C6 alkoxy group, (1-6) a cyano group, and (1-7) aC1-C6 alkoxy group.
 5. The method according to claim 4, wherein in thecompound represented by the formula (1) or a pharmaceutically acceptablesalt thereof is selected from(4aS,8aR)-1-(4-chlorophenyl)-3,3-dimethyldecahydroquinoxaline,2-chloro-4-((4aS,8aS)-3,3-dimethyloctahydroquinoxalin-1(2H)-yl)benzonitrile,(4aS,8aR)-1-(3-chloro-4-fluorophenyl)-3,3-dimethyldecahydroduinoxaline,(4aS,8aR)-1-(7-fluorobenzofuran-4-yl)-3,3-dimethyldecahydroduinoxaline,5-((4aR,8aS)-3,3-dimethyloctahydroquinoxalin-1(2H)-yl)-1-methyl-1H-indole-2-carbonitrile,(4a′R,8a′S)-4′-(7-methoxybenzofuran-4-yl)octahydro-1′H-spiro[cyclobutane-1,2′-quinoxaline],(4aS,8aR)-1-(6,7-difluorobenzofuran-4-yl)-3,3-dimethyldecahydroquinoxaline,5-((4aS,8aS)-3,3-dimethyloctahydroduinoxalin-1(2H)-yl)-1H-indole-2-carbonitrile,6-((4aS,8aS)-3,3-dimethyloctahydroduinoxalin-1(2H)-yl)-2-naphthonitrile,(4aS,8aS)-3,3-dimethyl-1-(1H-pyrrolo[2,3-b]pyridin-4-yl)decahydroquinoxaline,(4aS,8aS)-1-(4-(difluoromethoxy)-3-fluorophenyl)-3,3-dimethyldecahydroquinoxaline,(4aS,8aS)-1-(4-(difluoromethoxy)phenyl-3,3-dimethyldecahydroquinoxaline,and(4aR,8aR)-1-(4-difluoromethyoxy)-3-fluorophenyl-3,3-dimethyldecahydroquinoxaline.6. The method according to any one of claims 1, and 2 to 5, wherein thedepression is selected from the group consisting of major depressivedisorder; bipolar I disorder; bipolar II disorder; mixed state bipolardisorder; dysthymic disorder; rapid cycler; atypical depression;seasonal affective disorder; postpartum depression; hypomelancholia;recurrent brief depressive disorder; refractory depression; chronicdepression; double depression; alcohol-induced mood disorder; mixedanxiety-depressive disorder; depression caused by a physical disease,selected from the group consisting of Cushing('s) syndrome,hypothyroidism, hyperparathyroidism, Addison's disease,amenorrhea-galactorrhea syndrome, Parkinson's disease, Alzheimer'sdisease, cerebrovascular dementia, brain infarct, brain hemorrhage,subarachnoid hemorrhage, diabetes millitus, virus infection, multiplesclerosis, chronic fatigue syndrome, coronary artery disease, pain, andcancer; presenile depression; senile depression; depression in childrenand adolescents; and depression induced by drugs.
 7. The methodaccording to claim 6, wherein the depression is depression caused by aphysical disease selected from the group consisting of Cushing('s)syndrome, hypothyroidism, hyperparathyroidism, Addison's disease,amenorrhea-galactorrhea syndrome, Parkinson's disease, Alzheimer'sdisease, cerebrovascular dementia, brain infarct, brain hemorrhage,subarachnoid hemorrhage, diabetes millitus, virus infection, multiplesclerosis, chronic fatigue syndrome, coronary artery disease, pain andcancer.